Other entities represented in this entry:
HGNC Approved Gene Symbol: DMD
SNOMEDCT: 387732009, 702424003, 76670001;
Cytogenetic location: Xp21.2-p21.1 Genomic coordinates (GRCh38): X:31,119,222-33,339,388 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp21.2-p21.1 | Becker muscular dystrophy | 300376 | X-linked recessive | 3 |
| Cardiomyopathy, dilated, 3B | 302045 | X-linked | 3 | |
| Duchenne muscular dystrophy | 310200 | X-linked recessive | 3 |
The DMD gene encodes dystrophin, a large muscle protein that is mutant in Duchenne (310200) and Becker (300376) muscular dystrophy, defined as progressive deterioration of muscle tissue and resultant weakness.
The study of Duchenne and Becker muscular dystrophy resulted in one of the first successful attempts at reverse genetics, better described as positional cloning, in humans. (The other disorder was chronic granulomatous disease (306400), which is also X-linked and yielded to positional cloning in 1986.) Discovery and subsequent analysis of the gene mutation that results in the clinical disorder led to the discovery of the encoded protein, dystrophin. This coinage set a precedent for the naming of proteins discovered by positional cloning of human disease genes: for example, huntingtin, emerin, and ataxin.
Wood et al. (1987) noted that the gene for Duchenne muscular dystrophy, symbolized DMD (the same abbreviation as that used for the disorder Duchenne muscular dystrophy) encodes an mRNA of about 16 kb; thus, if the message encodes a single protein, it would be about 500 kD in size. The largest proteins in muscle then known were nebulin (550 kD) and titin (over 1000 kD). Both proteins are located at the junction of the A band (the area of the sarcomere composed of myosin thick filaments) and I band (the area of the sarcomere containing actin thin filaments attached to the Z line). Wood et al. (1987) found that the band identified as nebulin (161650) was absent or extremely faint in all 30 patients with DMD whereas it was clear in all controls, and the bands of all other proteins seen in control muscle were equally prominent in muscle from patients with DMD. Specifically, titin (188840) was equally prominent in control and DMD muscle. The authors suggested that nebulin may be the defective gene product in DMD; this is now known not to be the case.
Furst et al. (1987) concluded that nebulin and titin are expressed normally in DMD; monoclonal antibodies showed normal staining patterns on frozen sections of 3 muscle biopsies of DMD. This finding was confirmed by the observation of Pernelle et al. (1988), who studied the electrophoretic pattern of myofibrillar proteins from a child with an interstitial deletion of Xp21.2 and the phenotype of Duchenne muscular dystrophy associated with glycerol kinase deficiency, congenital adrenal hypoplasia, and severe mental retardation.
Hoffman et al. (1987) sequenced approximately 25% of the total 14-kb DMD transcript from human fetal skeletal muscle and mouse adult heart. The nucleic acid and predicted amino acid sequences from the 2 species were nearly 90% homologous. The amino acid sequence suggested that the protein product may serve a structural role in muscle, but the abundance and tissue distribution of the mRNA suggested that the DMD protein is not nebulin. This was conclusively established when the nebulin gene was localized to chromosome 2 (see 161650).
Koenig (1987) initially suggested from sequence similarities that the gene that is mutant in DMD may be that encoding alpha-actinin. Hammonds (1987) found similarity between the DMD protein and chicken alpha-actinin. Alpha-actinin is a normal component of actin filaments in smooth and skeletal muscle and may be involved in both crosslinking F-actin within the filaments and connecting filamentous elements of the cytoskeleton to the cell membrane. Alpha-actinin is divided into 2 domains, an amino-terminal domain, which binds actin, and a carboxy-terminal repetitive domain, which dimerizes in an antiparallel fashion to form a rod (Koenig et al., 1988).
Hoffman et al. (1987) identified the protein product of the human and mouse DMD loci by using polyclonal antibodies directed against fusion proteins reflecting 2 distinct regions of the mouse cDNA. The protein, called dystrophin, is about 400 kD in size and represents about 0.002% of total striated muscle protein; it is associated with the triadic junctions in skeletal muscle and is therefore probably involved with calcium ion homeostasis. The protein was also detected in smooth muscle of stomach. Both the muscle- and brain-type dystrophin isoforms are 427-kD proteins translated from 14-kb mRNAs.
Koenig et al. (1988) reported the complete sequence of dystrophin cDNA. The gene encodes a 3,685-amino acid protein product with 4 distinct domains and shares many features with spectrin and alpha-actinin. The authors predicted that the protein is likely to adopt a rod shape approximately 150 nm long.
The C terminus of the dystrophin protein is encoded by a highly conserved, alternatively spliced region of the gene. Bies et al. (1992) used unusual cases of deletions in the 3-prime region of the gene to unravel the function of the dystrophin molecule. A patient with infantile-onset DMD and cognitive impairment suggesting central nervous system disease was found to have an internal 3-prime genomic deletion of 1,824 bp which precisely excised the cysteine-rich and alternatively spliced COOH-terminal domains of dystrophin. Immunocytochemical analysis displayed dystrophin protein staining at the sarcolemma. This experience and the findings in other reported COOH-terminal deletions indicated that the cysteine-rich domain confers an important function for the dystrophin protein.
Zubrzycka-Gaarn et al. (1988) found that antibodies directed against synthetic peptides and fusion proteins derived from the N-terminal region of human dystrophin cDNA strongly reacted with the antigen present in skeletal muscle sarcolemma on cryostat sections of normal human muscle biopsies. This immunoreactivity was absent or reduced in muscle fibers from DMD patients but appeared normal in muscle fibers from patients with other myopathic diseases. These findings indicate that dystrophin is associated with the sarcolemma rather than with the triads. Zubrzycka-Gaarn et al. (1988) speculated that dystrophin strengthens the sarcolemma by anchoring elements of the internal cytoskeleton to the surface membrane.
Worton (1994) pointed out that it is unknown if dystrophin plays a purely mechanical role in providing strength to the skeletal muscle membrane or whether its role is more subtle. The biologic role of dystrophin might be, for example, to maintain a particular spatial distribution of the glycoprotein complex. From its amino acid sequence, dystrophin is similar to spectrin and other cytoskeletal proteins: rather like an I-beam with globular domains at each end, joined by a rod-like segment in the middle. At the NH2-end, dystrophin binds to cytoplasmic actin filaments (not actin of the contractile apparatus); at the other end, it is bound to a complex of proteins and glycoproteins that copurify with dystrophin from muscle membranes. The components of this complex are called dystrophin-associated proteins (DAPs) and dystrophin-associated glycoproteins (DAGs). These have been given individual names according to their molecular weights: 25DAP, 35DAG, 43DAG, 50DAG, 59DAP, and 156DAG. The 59DAP seems to be on the inside of the cell and binds directly to dystrophin. The 156DAG, also called dystroglycan or DAG1 (128239), seems to be totally outside the cell, is covered with sugar groups, and binds to laminin, a major component of the extracellular matrix.
Ishikawa-Sakurai et al. (2004) analyzed the C-terminal binding domain of dystrophin and demonstrated that the beta-dystroglycan binding activity is expressed by the dystrophin fragment spanning amino acids 3026-3345 containing the ZZ domain. The ZZ domain binds to EF1 domain in the dystrophin fragment to reinforce the binding activity. The cysteine residue 3340 in the ZZ domain is essential for the binding of dystrophin to beta-dystroglycan. Ishikawa-Sakurai et al. (2004) suggested that in the case of DMD due to missense mutation C3340Y (300377.0026) reported by Lenk et al. (1996), the mutation may have resulted in dissociation of dystrophin and beta-dystroglycan and concomitant inability to fix dystrophin beneath the cell membrane. The binding mode of utrophin (128240) differed from that of dystrophin with respect to the cysteine residues present in the ZZ domain.
Nonmuscle Dystrophin
Using a cDNA-PCR method to detect and quantitate minute amounts of mRNA, Chelly et al. (1988, 1989) found a ubiquitous basal level of transcription of tissue-specific genes in every cell type. They called the phenomenon illegitimate transcription. Sarkar and Sommer (1989) referred to it as ectopic transcription and showed that lymphoblasts, lymphocytes, and fibroblasts had bona fide versions of normal tissue-specific mRNAs. Chelly et al. (1991) extended these observations to demonstrate that abnormal transcripts such as the truncated DMD transcripts in muscular dystrophy patients likewise were demonstrable in bona fide form in nonmuscle cultured cells. Obviously, this provides useful material for diagnosing genetic abnormality and for investigating the qualitative consequences of gene defects at the mRNA level.
Kaplan et al. (1992) listed 17 genes for which illegitimate transcription had been documented; in 9 of these it had been used in the diagnosis of a genetic disorder. Caution in the use of ectopic transcription was suggested by the report by Roberts et al. (1993) of lack of fidelity. They described the inclusion of a novel exon in 50% of ectopic dystrophin transcripts from human peripheral blood lymphocytes. The novel sequence resembled a conserved region in the 3-prime untranslated region of members of the carcinoembryonic antigen gene family (114890) and lay within the first intron of the DMD gene. This constituted a significant departure from the expected in vivo splicing behavior in an ectopic transcript and suggested that there may be exceptions to the assumption that ectopic transcripts are processed in a similar manner to their tissue-specific counterparts. Perhaps one would expect that infidelity would be involved in the production of illegitimate transcripts.
The finding of dystrophin mRNA in brain may explain mental retardation in DMD patients (Chamberlain et al., 1988). Dystrophin in brain is transcribed from a different promoter from that used in muscle. Chelly et al. (1990) demonstrated that the brain-type promoter of the dystrophin gene is highly specific to neurons. By contrast, the muscle-type promoter is active in a wider range of cell types, including not only striated and smooth muscle, but also glial cells to a lesser extent, and probably neurons.
In the brain, dystrophin is localized subcellularly to the postsynaptic density, a disc-shaped structure that is believed to stabilize the synapse by anchoring postsynaptic receptors and by transducing signals. Kim et al. (1995) demonstrated that 427-kD dystrophin was absent from the postsynaptic densities in the brain of a patient with Duchenne muscular dystrophy, but was present in the brain of an age-matched control.
Bar et al. (1990) identified a 6.5-kb mRNA transcribed from the DMD gene that seems to be the major DMD gene product in many nonmuscle tissues, including brain, and apparently is regulated by a different promoter. Boyce et al. (1991) isolated the genomic region encoding the alternative 5-prime terminus of dystrophin in brain. Physical mapping of the alternative promoter indicated that it is located more than 90 kb 5-prime to the promoter used in muscle and 400 kb from exon 2 to which it is spliced. The large physical distance between the 2 promoters, taken together with their known tissue selectivities, suggested to Boyce et al. (1991) that in certain patients a deletion of either dystrophin promoter might give rise to reduced dystrophin expression selective to brain or muscle. They identified one such individual with specific deletion of the dystrophin muscle promoter (300377.0002), giving rise to Becker muscular dystrophy, and they predicted that specific loss of the brain promoter may be one cause of X-linked mental retardation. Using a probe from the 5-prime end of the DMD gene, Scott et al. (1988) found mRNA in both normal and DMD muscle, particularly in regenerating muscle fibers. The finding of signal for the 5-prime end of the transcript indicates that none of the DMD patients sampled had a true null mutation.
Lederfein et al. (1992) cloned the entire coding sequence of the 6.5-kb mRNA and identified a protein in Western blots of cell extracts that comigrated with the in vitro translation product of the cloned cDNA. This protein, which differs greatly from dystrophin, seems to be a major product of the DMD gene; its level in several nonmuscle tissues is comparable to the amount of dystrophin in muscle. It is undetectable in skeletal muscle extracts. It contains the C-terminal and cysteine-rich domains of dystrophin, 7 additional amino acids at the N terminus, and some modifications formed by alternative splicing in the C-terminal domain. It lacks the entire large domain of spectrin-like repeats and the actin-binding N-terminal domain of dystrophin. As stated earlier, the 14-kb dystrophin transcript from the DMD gene, which encodes a 427-kD protein, is differentially spliced at the amino terminal end, giving rise to alternative transcripts expressed in muscle and brain.
Dp71, which consists of the 2 C-terminal domains of dystrophin, is the major nonmuscle product of the DMD gene and the major product of adult brain. To study the possible function of Dp71, which is controlled by an internal promoter, and its expression during development, Sarig et al. (1999) specifically inactivated its expression by replacing its first and unique exon and a part of the concomitant intron with a beta-galactosidase reporter gene. X-Gal staining of Dp71-null mouse embryos and tissues revealed a very stage- and cell type-specific activity of the Dp71 promoter during development and during differentiation of various tissues, including the nervous system, eyes, limb buds, lungs, blood vessels, vibrissae, and hair follicles. High activity of the Dp71 promoter often seemed to be associated with morphogenic events and terminal differentiation.
Blake et al. (1992) described a 4.8-kb transcript from the DMD gene locus that is ubiquitously expressed but is particularly abundant in schwannoma cells where dystrophin could not be detected. Sequencing demonstrated that the 4.8-kb transcript shares exons with the carboxy-terminal end of dystrophin but the 5-prime untranslated region is not contained within the dystrophin transcript. Blake et al. (1992) suggested that the 4.8-kb gene product be called apo-dystrophin-1 as its expression is distinct from the dystrophin 14-kb mRNA even though it is transcribed from the same locus. They identified a second carboxy-terminal-encoding transcript (apo-dystrophin-2) in a rat glioma cell line. Tinsley et al. (1993) cloned and sequenced a 2.2-kb transcript and demonstrated that the range of tissue expression of the so-called apo-dystrophin-3 is similar to that of the apo-dystrophin-1 transcript except in early development where it may have a unique function.
In a review, Ahn and Kunkel (1993) pointed out that expression of the large DMD gene is under elaborate transcriptional and splicing control. At least 5 independent promoters specify the transcription of their respective alternative first exons in a cell-specific and developmentally controlled manner. Three promoters express full-length dystrophin, while 2 promoters near the C terminus express the last domains in a mutually exclusive manner. Six exons of the C terminus are alternatively spliced, giving rise to several alternative forms. Genetic, biochemical, and anatomic studies of dystrophin suggested a number of distinct functions are subserved by its great structural diversity.
Torelli and Muntoni (1996) reported that exon 4 can be spliced out in skeletal and cardiac muscle and that the absence of exon 4 is apparently without functional consequences. They noted that there is published evidence that absence of a number of other exons from the dystrophin transcript, such as exons 71-74 as reported by Rafael et al. (1994) and exons 17-48 as reported by England et al. (1990), may also be compatible with dystrophin function. Torelli and Muntoni (1996) suggested that this information may be used for the construction of minigenes for cloning into viral vectors.
Bakker et al. (1987) reported 2 families in which a pERT87 (DXS164) deletion was transmitted to more than 1 offspring by women who showed no evidence for the mutation in their white blood cells. In 1 of the families, Bakker et al. (1987) showed that the deletion was identical in 2 sibs, thus indicating that the deletion had occurred during mitosis in early germline proliferation. Darras and Francke (1987) described a similar situation. They studied a 4-generation family containing males who had DMD due to an intragenic deletion. The deletion was present in 2 of 5 daughters of a woman who herself did not have the deletion. Haplotype analysis indicated that the deletion chromosome was transmitted from the unaffected father. Covone et al. (1991) demonstrated germline mosaicism for a deletion of the dystrophin gene, as reported by other workers. Darras et al. (1988) found germinal mosaicism in 3 of 32 families: one in which an affected male transmitted a partial deletion of the DMD gene to 2 of his 5 daughters as demonstrated by RFLP analysis (Darras and Francke, 1987) and confirmed by cDNA analysis; and 2 families with gonadal mosaicism in females. Darras and Francke (1988) described the standard patterns of restriction fragments and polymorphisms in the normal DMD gene and proposed a diagnostic approach which was used in the deletion analysis of the 32 aforementioned DMD/BMD families.
Norman and Harper (1989) concluded that 2.5% of heterozygotes for the Duchenne/Becker gene have symptoms. They estimated the prevalence of manifesting carriers to be 1 in 100,000 of the female population, a figure comparable to the prevalence of autosomal recessive limb-girdle muscular dystrophy. If the mutation rates in male and female gametes are equal, then twice as many girls as boys should have a newly mutated DMD gene; 2.5% of them would be expected to manifest it, presenting as isolated cases, and causing confusion with limb-girdle dystrophy. Norman and Harper (1989) suggested that females with proximal muscle weakness, grossly elevated creatine kinase, and calf hypertrophy in whom muscle biopsy shows primary muscle disease without other cause, such as mitochondrial cytopathy or glycogen storage disease, are likely to be manifesting carriers of the DMD gene even in the absence of a positive family history.
Kunkel et al. (1985) used a method of subtractive hybridization for cloning the specific DNA fragment absent in patients homozygous or hemizygous for chromosomal deletions. They applied the method to the DNA of the patient with a minute interstitial deletion of Xp who was reported by Francke et al. (1985). Bakker et al. (1985) used a series of 11 RFLP markers that bridge the DMD locus at distances varying between 3 and 20 cM. Ten of these were anonymous (arbitrary) DNA segments and one was ornithine transcarbamylase (OTC; 300461). A double crossover was detected in a DMD carrier and an affected male fetus was diagnosed at 12 weeks of gestation with a probable accuracy of more than 99%. Ray et al. (1985) used rRNA sequences as probes to clone the region spanning the translocation breakpoint in an X;21 translocation (Verellen-Dumoulin et al., 1984). The break in 21p was sited within a cluster of ribosomal RNA genes. The sequence derived from the X-chromosomal portion of the clone detects a RFLP that is closely linked to the DMD gene and uncovers chromosomal deletions in some males with DMD. In 7 of 9 cases, Boyd and Buckle (1986) found breakpoints in Xp21.2 but in 2 others the breakpoint appeared to be in Xp21.1. Nevin et al. (1986) reported an X;5(p21.2;q31.2) translocation in a female with DMD. They tabulated 8 earlier reports.
Bodrug et al. (1987) cloned, restriction-mapped, and sequenced the exchange points from the case of X;21 translocation reported by Verellen-Dumoulin et al. (1984). The translocation was found to be reciprocal but not conserved. A small amount of DNA was missing from the translocated chromosomes; 71 or 72 basepairs from the X chromosome and 16 to 23 basepairs from the 28S ribosomal gene on chromosome 21. Although a number of tumor-associated translocations had been studied in molecular detail, this was probably the first instance in which a constitutional translocation had been studied at the nucleotide level. By the time of this report, there were 20 known cases of DMD-BMD females with X-autosome translocations with breakpoints at Xp21. Bodrug et al. (1987) noted the presence of a CGGC tetranucleotide in the immediate vicinity of the breakpoint on the derivative X chromosome, which was repeated 6 times on chromosome 21 and once on the X chromosome. Although it was uncertain whether this limited homology could be used as an explanation for the translocation, it might have been a recognition site for an enzyme involved in the translocation process.
Chelly et al. (1988) described a deletion of chromosome Xp21 associated with Duchenne muscular dystrophy, glycerol kinase deficiency, and adrenal hypoplasia. A combination of pulsed field gel electrophoresis and Southern blot analysis using multiple probes linked to the DMD locus was used to refine mapping information in the region. The data were consistent with a 4-megabase deletion and suggested that the GK and AHC loci are distal to J66-H1 and proximal to L1. A band migrating in the region of human nebulin was seen on silver staining of SDS polyacrylamide gel muscle extracts from this child as well as from 5 other DMD muscle specimens.
Feener et al. (1991) identified (CA)-n polymorphism surrounding the upstream 'brain' promoter of the dystrophin gene. Because these repeats are highly polymorphic with PIC values ranging from 0.586 to 0.768, they should be useful for linkage analysis in families with DMD.
Using antidystrophin antibody prepared to the N-terminal portion of dystrophin, Towbin et al. (1991) demonstrated low abundance cardiac dystrophin but normal dystrophin in skeletal muscle in patients with X-linked dilated cardiomyopathy (CMD3B; 302045). The findings with use of C-terminal antibody were normal in both cardiac and skeletal muscle.
Zhang et al. (2007) identified 7 novel cryptic exons embedded in dystrophin introns that were amplified from dystrophin mRNA isolated from lymphocytes of patients with DMD. The novel exons were designated 1b, 1c, 18a, 29a, 63a, 67a, and 77a. Detailed characterization indicated that the 14 cryptic exons identified to date were shorter, had lower splicing acceptor and donor probability scores, and were generally weaker than authentic exons. However, the cryptic exons may have physiologic roles, since they were retained in mRNA.
Sabeti et al. (2007) reported an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2. The analysis revealed more than 300 strong candidate regions that appeared to have undergone recent natural selection. Examination of 22 of the strongest regions highlighted 3 cases in which 2 genes in a common biologic process had apparently undergone positive selection in the same population: LARGE (603590) and DMD, both related to infection by the Lassa virus, in West Africa; SLC24A5 (609802) and SLC45A2 (606202), both involved in skin pigmentation, in Europe; and EDAR (604095) and EDA2R (300276), both involved in the development of hair follicles, in Asia.
Prochniewicz et al. (2009) noted that utrophin (128240) and dystrophin bind actin with similar affinities, but the molecular contacts are different. Dystrophin utilizes 2 low-affinity actin-binding sites, whereas utrophin utilizes a continuous actin-binding domain. Using transient phosphorescence anisotropy, they showed that both proteins restricted the amplitude and increased the rate of actin bending and twisting. However, utrophin had a much greater effect than dystrophin in reducing actin torsional rigidity, particularly with high actin saturation. Utrophin, like dystrophin, had no effect on actin aggregation or bundling. Prochniewicz et al. (2009) hypothesized that, in addition to stabilizing actin filaments from depolymerization, dystrophin and utrophin provide greater resistance to actin filament breakage due to stretching or twisting.
Monaco et al. (1986) isolated more than 200 kb of DNA from the vicinity of the DMD gene and searched for cross-species DNA homology in Southern blots. They argued that any expressed exons would show evolutionary conservation and found 2 candidate probes that hybridized to DNA from all mammals tested. One of these probes, pERT-25, reacted with a 16-kb transcript that is present in fetal muscle RNA samples but is not detectable with mRNA from cultured human myoblasts or HeLa cells. Short, complementary DNA clones, isolated after screening a fetal muscle cDNA library with pERT-25, recognized exons distributed over more than 110 kb of DNA in the DMD region. Extrapolation suggested that the candidate DMD gene may be 1 to 2 million bases long. Messenger RNA as long as 16 kilobases had been found in only 1 instance before, namely, in apolipoprotein B (107730). Bakker and Pearson (1986) found what appeared to be an abnormally high frequency of mutations due to meiotic recombination, resulting in duplication/deficiency. Although the data did not reach the level usually accepted for statistical significance, the findings were very suggestive. The use of DNA markers in the region of the DMD locus permitted recognition of recombination.
Koenig et al. (1987) concluded that the DMD transcript is formed by at least 60 exons; the first half of the transcript is formed by a minimum of 33 exons spanning nearly 1000 kb, and the remaining portion has at least 27 exons that may spread over a similar distance. Among 104 DMD boys, DNA deletion was found in 53. Most deletions were concentrated in a single genomic segment corresponding to only 2 kb of the transcript. Worton (1987) had found duplications as well as deletions in the DMD locus. These are presumably created through unequal crossing-over within this very large gene.
Tennyson et al. (1995) stated that the DMD gene has 79 exons spanning at least 2,300 kb (2.3 Mb). They monitored transcript accumulation from 4 regions of the gene following induction of expression in muscle cell cultures. Quantitative RT-PCR results indicated that approximately 12 hours are required for transcription of 1,770 kb (at an average elongation rate of 2.4 kb per 6 seconds), extrapolating to a transcription time of 16 hours for the complete gene. Accumulation profiles for spliced and total transcript demonstrated that transcripts are spliced at the 5-prime end before transcription is complete, providing strong evidence for cotranscriptional splicing.
Hart et al. (1987) studied DNA of 33 patients suffering from Becker muscular dystrophy. Three were found to have deletions in DXS164, suggesting a frequency about the same as that for deletion in DMD. Of the 2 cases showing large deletions, one was at the severe end of the clinical spectrum for BMD. Monaco and Kunkel (1987) reviewed work on the DMD/BMD locus. The overall incidence of deletions (6.5%) was similar to the frequency found in other X-linked disorders such as Lesch-Nyhan syndrome, ornithine transcarbamylase deficiency (311250), and hemophilia A. From the orientation of the potential 5-prime and 3-prime splice sites in the human genomic sequence of the conserved region (Monaco et al., 1986) and the relationship of this sequence to the restriction map of the DXS164 locus that had previously been oriented on the short arm, the direction of transcription in the DMD gene was predicted to be from the centromere to the terminus of the short arm. The exons corresponding to the cDNA clones were predicted by Monaco and Kunkel (1987) to have an average size of less than 150 bp with an average intron size of 16 kb. From the ratio of the length of the cDNA clones to the genomic DNA of the DXS164 locus across which they hybridize, one can extrapolate that the large 16-kb transcript could correspond to as much as 1 to 2 million bp of genomic DNA. This is equivalent to approximately 0.05% of the human genome and one-half of an E. coli genome. Long-range mapping using pulsed field gel electrophoresis and restriction enzymes that cut at rare sites indicates that the X;6 and X;11 translocation breakpoints are more than 1,000 kbp apart.
Tuffery-Giraud et al. (2009) described a French database of mutations in the DMD gene that includes 2,411 entries consisting of 2,084 independent mutation events identified in 2,046 male patients and 38 expressing females. This corresponds to an estimated frequency of 39 per million with a genetic diagnosis of a 'dystrophinopathy' in France. Mutations in the database include 1,404 large deletions, 215 large duplications, and 465 small rearrangements, of which 39.8% are nonsense mutations. About 24% of the mutations are de novo events. The true frequency of BMD in France was found to be almost half (43%) that of DMD.
Among 624 index cases evaluated for DMD mutations, Oshima et al. (2009) reported that a genomic rearrangement was detected in 238 (38.1%) samples. Deletions were detected in 188 (79.0%), and included 31 cases with single-exon deletions and 157 cases with multi-exonic deletions. Most of the deletions fell between exons 45 and 52 and between exons 8 and 13 of the gene. Duplications were detected in 44 (18.5%) cases, of which 12 involved single exons and 32 multiple exons. Complex rearrangements were detected in 6 (2.5%) cases. The remaining 386 cases showed normal results. Oshima et al. (2009) selected 15 unique rearrangements, of which none shared a common breakpoint, and used array CGH and MLPA analyses to evaluate the mechanism of rearrangement. Fourteen of the deletions had microhomology and small insertions at the breakpoints, consistent with a mechanism of nonhomologous end joining (NHEJ) after DNA damage and repair. Analysis of 3 complex intragenic DMD gene rearrangements identified several features that could result in genomic instability, including breakpoints that aligned with repetitive sequences, an inversion/deletion involving a stem-loop structure, replication-dependent fork stalling and template switching (FoSTeS), and duplications causing secondary deletions.
Takeshima et al. (2010) reported the results of genomic, cDNA, and chromosome analysis of patients included in a Japanese DMD/BMD database. A mutation in the DMD gene was found in all 442 patients, including deletions and duplications in 270 (61%) and 38 (9%) cases, respectively; nonsense or splice site mutations in 69 (16%) and 24 (5%) cases, respectively; and small deletion/insertion mutations in 34 (8%) cases. X-chromosome abnormalities were identified in 2 cases, and unusual changes were found in 6 cases. The reading frame rule was upheld for 93% of deletion and 66% of duplication mutation cases. Induction of exon skipping was deemed the first priority for treatment of the dystrophinopathy.
Deletions
The most common type of disease-causing mutation of the DMD gene is deletion of 1 or more exons, identified in approximately 60 to 65% of patients (Oshima et al., 2009).
Gospe et al. (1989) described an extraordinary family with X-linked myalgia and cramps due to a nonprogressive myopathy associated with and presumably caused by a deletion in the dystrophin gene. Nine affected male family members had high resting serum levels of creatine kinase and well-developed musculature with calf hypertrophy but no evidence of muscular weakness. Symptoms began in childhood and did not progress. Electromyographic findings were consistent with myopathy while muscle biopsies showed nonspecific myopathic changes without evidence of storage of glycogen or lipid. Analysis of DNA showed deletion in the first third of the dystrophin gene. Western blot analysis showed that dystrophin was smaller than normal with, however, no reduction in the amount of the protein present. (Western blotting of protein with antibody was developed by Burnette (1981) and so-named in respect to the developer of DNA blotting, E. M. Southern (1975). Alwine et al. (1977) had developed the technique for blotting RNA and had dubbed the technique Northern blotting.)
Doriguzzi et al. (1993) described a patient who presented at the age of 9 years with exertional myalgias and a history of 2 episodes of myoglobinuria. At the age of 17 years, the patient had generalized muscle hypertrophy without muscle weakness. Genomic DNA analysis showed deletion of the HindIII fragment spanning from exon 45 to exon 48.
Minetti and Bonilla (1992) indicated that the mosaic pattern of normal and dystrophin-deficient fibers in muscle biopsy specimens from female heterozygotes can be seen not only in DMD carriers but also in carriers of the syndrome of familial X-linked myalgia and cramps reported by Gospe et al. (1989), as well as in carriers of Becker muscular dystrophy.
Using DNA markers, Lindlof et al. (1988) found deletions in 36% of Becker families and 8% of Duchenne families. Their study group had 37 DMD families and 11 BMD families. Using conventional Southern blots and field inversion gel electrophoresis (FIGE) analysis to study 34 Becker and 160 Duchenne muscular dystrophy patients, den Dunnen et al. (1989) found 128 mutations (65%), 115 deletions, and 13 duplications. They determined the size of the DMD gene to be about 2.3 million basepairs. Introns varied in size from a few kilobases to 160 to 180 kb for intron 44. In the study of Werner and Spiegler (1988), the X chromosomes of the proband's grandmother were normal, suggesting that the deletion in the mother was a new mutation. Read et al. (1988) found deletion of 1 or more exons in 60% of DMD and BMD patients. Half of all BMD patients had a deletion of 1 particular small group of exons; smaller deletions within the same group produced DMD.
McCabe et al. (1989) studied 1 of the 2 brothers first reported with the syndrome of dystrophic myopathy, glycerol kinase deficiency, and congenital adrenal hypoplasia. Genomic probes had not detected a deletion in this patient. With cDNA probes they demonstrated a deletion beginning at a position about 10.5 kb from the 5-prime end of the 14-kb DMD cDNA and extending through the 3-prime end of the DMD gene. Mao and Cremer (1989) showed that by dosage effect one can demonstrate the carrier status of female relatives of DMD patients showing a deletion within a DMD cDNA clone. Lindlof et al. (1989) studied 90 unrelated patients with DMD or BMD. These represented more than half the known families in Finland. Half the patients had deletion of 1 or several of the 65 exon-containing HindIII fragments. Using a wheelchair age of 12 years to distinguish between DMD and BMD, they found that the proportions of patients with deletions were similar. Furthermore, deletions were equally common in familial and sporadic disease. They found that BMD was more commonly caused by deletions in the 5-prime end of the gene than was DMD. If one assumes that unequal crossing-over between the 2 X chromosomes in female meiosis explains the generation of deletions, duplications should be generated at equal frequencies. However, in contrast to the high proportion of deletions found among DMD patients, duplications are relatively rare (Bettecken and Muller, 1989).
Baumbach et al. (1989) found that the frequency of deletions of the DMD gene was greater in affected males resulting from a female gametic mutation (75%) than in those resulting from a male gametic mutation (56%). By examining informative RFLPs flanking the site of deletion for evidence of recombination, they failed to detect evidence of illegitimate recombination associated with deletion formation in any of 12 cases studied.
Partial gene deletion or duplication in the DMD gene accounts for about 65% of cases of Duchenne muscular dystrophy. These mutations are clustered at 2 hotspots: 30% at the hotspot in the proximal part of the gene and about 70% at a more distal hotspot. Independent support for the different frequency in mosaicism cases was provided by comparing the mutation spectra observed in isolated cases of DMD and familial cases. In a 2-center study of 473 patients from Brazil and the Netherlands, Passos-Bueno et al. (1992) found that the ratio of proximal to distal deletions was 1:3 in isolated cases and 1:1 in familial cases. From these data they concluded that proximal deletions probably occur early in embryonic development, causing them to have a higher chance of becoming familial, while distal deletions occur later and have a higher chance of causing only isolated cases. Their findings suggested that a 'proximal' new mutant had an increased recurrence risk of approximately 30%, and a 'distal' new mutant a recurrence risk of approximately 4%.
The central portion of the dystrophin gene locus is a preferential site of deletions causing DMD. Intron 44, which is 160-180 kb long, is, for instance, the site of one breakpoint in about 30% of all DMD deletions (Baumbach et al., 1989). By sequencing a deletion junction fragment from a DMD patient, Pizzuti et al. (1992) demonstrated that the proximal breakpoint of the deletion in intron 43 fell within the sequence of a transposon-like element. This segment, belonging to the THE-1 family of human transposable elements, is normally present in a complete form in intron 43 of the DMD gene. The deletion mutation was maternally transmitted and eliminated two-thirds of the THE-1 element. One other patient with DMD and a proximal breakpoint mapping within the same THE-1 element was identified. The THE-1 element is 2.3 kb long and is flanked by 350-bp LTRs beginning with the sequence 5-prime-GT and ending with CA-3-prime (Paulson et al., 1985). THE-1 elements are classified as retrotransposons even though no homology to other retroviral sequences has been found (Finnegan, 1989). The complete element is represented 10,000 times in the genome.
In a girl with DMD and a cytologically balanced constitutional reciprocal translocation, t(X;4)(p21.2;q31.22), Giacalone and Francke (1992) found that the DMD gene was disrupted within the 18-kb intron 16. Restriction mapping and sequencing of clones that spanned both translocation breakpoints as well as the corresponding normal regions indicated the loss of approximately 5 kb in the formation of the derivative X chromosome, with 4 to 6 bp deleted from chromosome 4. RFLP and Southern analysis indicated that the de novo translocation was of paternal origin and that the father's X chromosome contained the DNA that was deleted in the derivative X. The deletion and translocation probably arose simultaneously from a complex rearrangement event that involved 3 chromosomal breakpoints. Short regions of sequence homology were present at the 3 sites. A 5-bp sequence, GGAAT, was found exactly at the translocation breakpoints on both normal chromosomes X and 4; this sequence had been preserved only on the derivative chromosome 4. The findings suggested a possible mechanism that may have juxtaposed the 3 sites and mediated sequence-specific breakage and recombination between nonhomologous chromosomes in male meiosis.
Hoop et al. (1994) found that 2 male cousins with Duchenne muscular dystrophy had different dystrophin haplotypes and different deletion mutations. In 1 of the cousins, there were 2 noncontiguous deletions: 1 in the 5-prime, proximal deletional hotspot region, and the other in the 3-prime, more distal deletional hotspot region. The second cousin showed only the 5-prime deletion. Hoop et al. (1994) showed that the mother of each propositus carried both deletions on the same grandmaternal X chromosome. The discrepant findings in the 2 cousins was explained by a single recombinational event between the 2 deleted regions of 1 of the carrier's dystrophin genes, giving rise to a son with a partially 'repaired' gene retaining only the 5-prime deletion.
Takeshima et al. (1994) reported a Japanese boy with clinical symptoms intermediate between those of Duchenne and Becker muscular dystrophy. There was a large in-frame deletion extending from exons 3 to 41 of the dystrophin gene, and there was no demonstrable binding to antibodies against the amino-terminal end. The authors speculated that the increased severity of the disease could be due to the lack of the actin-binding domain of dystrophin.
Muntoni et al. (1993) demonstrated that an X-linked form of dilated cardiomyopathy (CMD3B; 302045) was due to deletion in the promoter region and first exon of the DMD gene (300377.0021).
Duplications
In 2 patients with DMD and 1 with BMD, Hu et al. (1988) found a duplicated region within the locus by Southern blot analysis and transmission densitometry. In 2 cases a new restriction fragment spanning the duplication junction was visualized, indicating that the duplications were tandemly arranged. Mendelian inheritance was shown in these 2 families by following the segregation of the duplication junction fragment. They showed that all 3 duplications are internal to the gene and thus can result in a genetic disorder through disruption of exon organization.
Hu et al. (1989) reported 3 families, each containing a male with Duchenne or Becker muscular dystrophy and each showing that an exon-containing segment of DNA within the DMD gene was duplicated in the probands, their mothers, and, in 2 cases, their sisters. The grandpaternal origin of the duplication was demonstrated by RFLP and duplication analysis. The results suggested that unequal sister chromatid exchange, which most likely occurred in the germ cell lineage of the proband's grandfather, is responsible for generating these duplications, and that this type of intrachromosomal rearrangement is common in the muscular dystrophy gene. Hu et al. (1990) identified 10 cases of partial duplication of the DMD gene, giving a frequency of 14% for nondeletion cases (10/72), or 6% for all cases (10/181). They demonstrated a grandpaternal origin of the duplication in 4 families and a grandmaternal origin in 1 family. In all 5 families, the duplication originated from a single X chromosome; thus, unequal sister chromatid exchange may be the mechanism of the duplications.
In a patient with Becker muscular dystrophy, Angelini et al. (1990) found a duplication of the DMD gene of more than 400,000 bp. The duplication was completely contained within the gene, and the duplicated exons were predicted to be in frame. Dystrophin protein was detected in the patient's muscle as a single species of approximately 600 kD, as compared with a normal of about 400, indicating that the mutated gene encodes a translatable mRNA of over 100 exons, as compared to the normal of about 70 exons. The mother carried the duplicated gene as indicated by both DNA and protein analysis. This dystrophin gene and the protein it encodes, called dystrophin Friuli after the Italian region where the family originated, was the largest characterized to the time of the report. Using polymorphic loci that lie at the 2 extremities of the DMD gene, Abbs et al. (1990) estimated the intragenic recombination rate to be nearly 0.12 (confidence intervals, 0.041-0.226) over the genomic length of approximately 2 Mb.
Hu and Worton (1992) reviewed partial gene duplication as a cause of human disease. Gene duplication was recognized as an important mechanism of evolution by Ingram (1961), who studied hemoglobins, by Smithies et al. (1962), who studied the haptoglobin genes, and by Ohno (1970), who gave a general discussion. Protein amino acid sequence comparisons provided clues that many proteins are related by common ancestry (Doolittle, 1981). The first reported patient carrying a partial gene duplication was a male with Lesch-Nyhan syndrome (Yang et al., 1984); see 308000.0047. As reviewed by Hu and Worton (1992), partial duplication has been observed in a number of other diseases. Partial duplication of the DMD gene is responsible for 6 to 7% of mutations causing Duchenne and Becker muscular dystrophy. In general, the rule that when the reading frame is not disrupted the phenotype is Becker muscular dystrophy, whereas frameshift causes the more severe form of disease, holds true. Both in-frame and frameshift gene duplications have been observed in other disorders as well. Hu and Worton (1992) stated that 2 of 8 disease-causing duplications in which sequence analysis of the duplication junction had been performed were found to represent homologous recombination between Alu elements, causing in one case familial hypercholesterolemia (143890) and in the other case DMD (Hu et al., 1991). In the other 6 cases, recombination between the nonhomologous sequences was involved. In these cases, type I and type II topoisomerases may play a role; the evidence comes from the fact that the preferred topoisomerase cleavage sites have been identified at the breakpoints on both parental strands.
White et al. (2006) identified 118 duplications in the DMD gene among over 230 patients with DMD/BMD. In an unselected patients series, the duplication frequency was 7%; in patients previously screened for deletions and point mutations, the duplication frequency was 87%. Duplication frequency was highest near the 5-prime end of the gene, with a duplication of exon 2 being the single most common duplication identified. Sequence analysis of 4 exon 2 duplication breakpoints showed that they did not arise from unequal sister chromatid exchange, but more likely from synthesis-dependent nonhomologous end joining.
Point Mutations
Lenk et al. (1993) applied PCR-SSCP analysis to exons 60-79 of the DMD gene in 26 DMD/BMD patients without detectable deletions. The study identified 7 point mutations and 1 intron polymorphism. Premature translational termination was predicted by 6 of the point mutations found in DMD patients. One point mutation, identified in a BMD patient, resulted in an amino acid exchange. Mental retardation was present in 5 of the DMD patients bearing a point mutation, suggesting that a disruption of the translational reading frame in the C-terminal region is particularly associated with this clinical finding in DMD cases. The authors raised the possibility that Dp71 and/or Dp116, the C-terminal translational products of the DMD gene, may be causally involved in cases of mental retardation associated with DMD. In this connection, Lederfein et al. (1993) pointed out that Dp71, the 70.8-kD protein product of the distal part of the DMD gene, is expressed in many cell types and tissues. They used anchored PCR, primer extension and functional analysis of transfected constructs to determine the 5-prime end of the mRNA and characterized the promoter of Dp71. The 5-prime untranslated region of Dp71 is transcribed from a single exon; the promoter does not contain a TATA box and has a very high GC content and several potential Sp1 binding sites. It is located more than 2 Mb 3-prime to the muscle- and brain-type dystrophin promoters and only 150 kb from the 3-prime end of the DMD gene, suggesting that in most DMD patients the expression of Dp71 is unaffected.
Roberts et al. (1992) described a general approach to the identification of the basic defect in the one-third of DMD patients who do not show a gross rearrangement of the dystrophin gene. The method involved nested amplification, chemical mismatched detection, and sequencing of reverse transcripts of trace amounts of dystrophin mRNA from peripheral blood lymphocytes. Analysis of the entire coding region (11 kb) in 7 patients resulted in detection of a sequence change in each case that was clearly sufficient to cause the disease. All the mutations were expected to cause premature translation termination, and the resulting phenotypes were thus equivalent to those caused by frameshifting deletions; see 300377.0003-300377.0009.
By means of chemical mismatch cleavage applied to 13 exons amplified in multiplex sets by PCR, Kilimann et al. (1992) likewise sought point mutations in 60 DMD patients without detectable deletions or duplications. The analysis was estimated to cover approximately 20% of the dystrophin-coding sequence. They identified 2 point mutations and 4 polymorphisms. Both point mutations were frameshift mutations, in exons 12 and 48, respectively, and were closely followed by stop codons, thus explaining the functional deficiency of the dystrophin gene product. Using fluorescent PCR products analyzed on an automated sequencer, Schwartz et al. (1992) developed a fast and accurate PCR-based linkage and carrier detection method for use in families with DMD or BMD with or without detectable deletions of the dystrophin gene. When the deletion was found in the affected male by standard multiplex PCR, fluorescently labeled primers specific for the deleted and nondeleted exons were used to amplify the DNA of at-risk female relatives by using multiplex PCR at low cycle number (20 cycles). The products were then quantitatively analyzed on an automated sequencer to determine whether they were heterozygous for the deletion and thus represented carriers. As a confirmation of the linkage data, and in cases in which a deletion was not found in the proband, fluorescent multiplex PCR linkage was done by use of 4 previously described polymorphic dinucleotide (CA)n repeats located throughout the dystrophin gene.
Roberts et al. (1994) reviewed the molecular etiology of the one-third of cases of DMD and BMD that are associated with small mutations. They reviewed 70 such mutations and marveled at the fact that for such a well-conserved gene, missense mutations are very rare. The vast majority of DMD point mutations, like the gross rearrangements, result in premature translation termination, i.e., are nonsense mutations. It seems likely that most cases of DMD arise as a result of a reduction in the level of dystrophin transcripts. Most of the few BMD point mutations reviewed were missense mutations in the N-terminal or C-terminal domains or were splice site mutations that probably act, like BMD deletions, via the production of in-frame, interstitially deleted transcripts.
More than 60% of DMD and BMD mutations are deletions of variable size. Higher deletion frequencies have been reported for 2 groups of contiguous exons in the 5-prime and central portions of the gene; these are referred to as the 'minor' and 'major' deletion hotspots, respectively. Increased breakpoint frequency near the 5-prime end of the gene directly correlates with the large sizes of some introns, whereas in the central intragenic region, the highest density of deletion breakpoints (number of breakpoints per intron length) occurs between exons 45 and 51 (Nobile et al., 1997). One of the smaller introns from this region, intron 49, exhibits a breakpoint density 4 to 5 times higher than those of introns 7 and 44. To determine the mechanisms leading to deletions in intron 49, Nobile et al. (2002) sublocalized 22 deletion breakpoints along its length. They found that breakpoints were uniformly distributed throughout the intron length, and no extensive homology was observed between the sequences adjacent to each breakpoint. However, a short sequence able to curve the DNA molecule was found at or near 3 breakpoint junctions.
Deletions and point mutations in the DMD gene cause either DMD or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. De Angelis et al. (2002) reasoned that because internal in-frame deletions in the protein produce only mild myopathic symptoms, a partially corrected phenotype could be restored by preventing the inclusion of specific mutated exons in the mature dystrophin mRNA. Such control had previously been accomplished by the use of synthetic oligonucleotides. To circumvent the disadvantageous necessity for periodic administration of the synthetic oligonucleotides, De Angelis et al. (2002) produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. They showed that antisense molecules against exon 51 splice junctions were able to direct skipping of that exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. They also showed that the highest skipping activity occurred when antisense constructs against the 5-prime and 3-prime splice sites were coexpressed in the same cell. The effects were tested in cultured myoblasts from a DMD patient. The deletion of exons 48-50 resulted in a premature termination codon in exon 51. The antisense sequences complementary to exon 51 splice junctions induced efficient skipping of exon 51 and partial rescue of dystrophin synthesis.
Aartsma-Rus et al. (2004) noted that a series of antisense oligonucleotides (AONs) had been identified that could be used to induce the skipping of 20 different DMD exons that would, theoretically, be beneficial for more than 75% of all DMD patients. To further enlarge this proportion, they studied the feasibility of double and multiexon skipping. In one patient, with an exon 46-50 deletion, the therapeutic double skipping of exon 45 and 51 was achieved. Remarkably, in control myotubes, the latter combination of AONs caused the skipping of the entire stretch of exons from 45 through 51. This in-frame multiexon skipping would be therapeutic for a series of patients carrying different DMD-causing mutations. In fact, they demonstrated its feasibility in myotubes from a patient with an exon 48-50 deletion. The application of multiexon skipping may provide a more uniform methodology for a larger group of patients with DMD.
In a male with DMD, Van Essen et al. (2003) identified a point mutation in the DMD gene (300377.0078) for which the mother was mosaic. They stated that germline mosaicism for point mutations in DMD had been reported only twice previously (see 300377.0022 and Smith et al., 1999).
Buzin et al. (2005) performed a mutation analysis in 141 DMD patients previously found to be negative for large deletions by standard multiplex PCR assays. Comprehensive mutation scanning of all coding exons, adjacent intronic splice regions, and promoter sequences was performed by a method that detected essentially all point mutations. Samples negative for point mutations were further analyzed for duplications. Presumptive causative mutations were detected in 90% of the patients: 70% were protein truncating point mutations, 13% duplications, and 7% deletions. Forty of the mutations were putatively novel. Buzin et al. (2005) stated that this was the first analysis of the absolute and relative rates of point mutations in the dystrophin gene. Relative to microdeletions, which had a frequency of 0.68 x 10(-9) per bp per generation, transitions at CpG dinucleotides were enhanced 150-fold, whereas complex insertions/deletions (indels), the least common mutation type, were less frequent than microdeletions by a factor of 5. The frequency of microdeletions and microinsertions at mononucleotide repeats was found to increase exponentially with length. When compared to the well-studied human factor IX gene (F9; 300746), the results were similar, with 2 exceptions: a hotspot of mutation in the dystrophin gene at a CpG dinucleotide, an 8713C-T transition resulting in an arg2905-to-ter substitution (R2905X; 300377.0082), and an altered size distribution of microdeletions. A mutation rate of approximately 1.7 x 10(-6) per nucleotide per generation for the 8713C-T hotspot mutation in the DMD gene was similar to the rates of 3 of the most highly mutable nucleotides known in the human genome: 8.2 x 10(-6) for the CpG 1138G-A transition in the FGFR3 gene (134934.0001), causative for achondroplasia (100800); 5 x 10(-6) for the CpG 934C-G transversion in the FGFR2 gene (176943.0010), causative for Apert syndrome (101200); and 2.7 x 10(-6) for a 937C-G transversion also in FGRF2 (176943.0011), although not at a CpG, and also causative of Apert syndrome. The hotspot mutations in the FGFR genes account for more than 97% of the disease-causing mutations in those genes, but the dystrophin gene has a wide variety of point mutations in addition to the hotspot mutation.
Milasin et al. (1996) reported a family with X-linked dilated cardiomyopathy (302045) with a point mutation in the 5-prime splice site of the dystrophin E1-I1 boundary (300377.0025).
In a 12-year-old boy with asymptomatic dystrophinopathy (see 300376), Yagi et al. (2003) identified a point mutation in intron 2 of the DMD gene (300377.0083) that creates an AG dinucleotide consensus sequence for a splicing acceptor site predicted to produce a novel exon structure that is then incorporated into dystrophin mRNA. Yagi et al. (2003) stated that the creation of a splice acceptor site by a single nucleotide change leading to an extra exon structure is a novel molecular mechanism in human disease.
Nishiyama et al. (2008) found that 7 (18%) of 38 nonsense mutations in the DMD gene resulted in partial skipping of the nonsense-encoding exon and alternative splicing of dystrophin mRNA in cultured lymphocytes. Five of these aberrant splice products were predicted to lead to a semifunctional protein, but only 1 of the patients had a mild phenotype. However, dystrophin mRNA was not analyzed in muscle. The data also showed that patients with the same nonsense mutation exhibited differences in rescue transcript production, suggesting that there are individual differences in the regulation of splicing between patients.
Legardinier et al. (2009) analyzed the functional consequences of 2 mutations in the rod domain repeat 23 (R23) region encoded by exon 59 and corresponding to residues 2800 to 2939 of the DMD protein. In vitro studies showed that the E2910V (300377.0061)/N2912D (300377.0062) double-mutant protein showed substantially lower thermal and chemical stability and slower refolding compared to the wildtype protein. The variation in the double mutant compared to wildtype was larger than those observed for the single mutants. The mutations appeared to impact the electrostatic potentials stabilizing the triple alpha-helix coiled-coil repeat. Legardinier et al. (2009) concluded that changes in stability of a repeat from the rod domain could explain the loss of mechanical properties of dystrophin and defects in muscle cells. (The E2910V and N2912D variants have been reclassified as variants of unknown significance.)
The major consequences of mutations at splice sites are exon skipping and cryptic splice site activation. By in vitro splicing analysis, Habara et al. (2009) found that +1G-A splice site mutations in intron 25 (3432+1G-A) and intron 45 (6614+1G-A) of the DMD gene did not always cause the same effect. The 3432+1G-A mutation in intron 25 resulted in exon skipping and a milder Becker phenotype, whereas the 6614+1G-A mutation in intron 45 produced 3 products due to the use of cryptic donor sites and resulted in a more severe Duchenne phenotype. In silico analysis of 13 additional +1G-A splice site mutations reported in the literature (see, e.g., 300377.0066; 300377.0068), plus the 2 mutations in the current study, showed association with exon skipping in 11 and association with cryptic splice sites in 4. Habara et al. (2009) concluded that the combination of high acceptor splice site score and longer exon length is a major factor determining splicing pathways in such mutations in the dystrophin gene, and that mere availability of a cryptic splice site is not sufficient to determine the splicing pathway.
Using the cloned DNA segment DXS164 (pERT 87), Kunkel (1986) tested the frequency of deletions discovered in DNA from DMD/BMD boys and the accuracy of this cloned segment in determining the inheritance of DMD. (Kunkel's published report represented 76 persons working in some 24 institutions in many parts of the world.) In all, 1,346 cases were studied; deletion was revealed by this probe in 88 (6.5%): 54 cases of deletion in 650 familial DMD cases (8.3%); 32 in 551 sporadic DMD cases (5.8%); and 2 in 145 BMD cases (1.4%). DXS164 recombines with DMD 5% of the time, it seemed, but was thought to be located between independent sites of mutation which yield DMD. The breakpoints of some deletions were delineated within the DXS164 segment. Clearly, deletions at the DMD locus are frequent and unusually large (most of them more than 137 kb). The fact that deletion of DXS164 was found also in 2 cases of BMD indicated that DMD and BMD are either allelic or very closely linked.
Forrest et al. (1987) increased to 40% the proportion of families in which deletions could be detected. Most of these deletions were found to begin in the same region of the cDNA, which implies that there is a common mechanism for the generation of many of them. An apparently identical deletion in 1 family gave classic BMD in 2 brothers (presenting in their teens) and only very mild muscle weakness in their 86-year-old great-great-uncle. It is particularly significant that Forrest et al. (1987) used cDNA subclones of the DMD gene in the screening. The finding of a higher frequency of deletion indicates that there is a preferential deletion of exons in DMD and BMD. Using field inversion gel electrophoresis (FIGE), den Dunnen et al. (1987) detected structural abnormalities of the DMD gene in 21 of 39 DMD cases, of which 14 were not detected by 'conventional' methods. A region prone to deletion was found in the distal half of the gene. Koh et al. (1987) described a curious family in which the mother was carrying a deletion of the DMD locus; she transmitted that chromosome to both of her sons, but only 1 of the 2 was affected. Using probes for about 25% of the proximal part of the dystrophin gene, Bartlett et al. (1988) found deletions in 23% of DMD boys, and a single distal probe detected 17% more as deletions.
Liechti-Gallati et al. (1987) described a BMD case with deletion of the pXJ region, the first in this location in the 'DMD' locus. The deletion originated from the maternal grandfather. Hoffman et al. (1988) presented evidence that there is a quantitative abnormality of dystrophin, i.e., very low levels or absence, in cases of severe Duchenne phenotype and low concentrations of dystrophin in the intermediate (or outlier) phenotype. On the other hand, in Becker dystrophy, there is a qualitative abnormality of dystrophin, namely, abnormal molecular weight. Other neuromuscular disorders showed normal levels of dystrophin.
Hoffman et al. (1987) demonstrated that in DMD dystrophin is totally absent whereas in BMD an abnormal (usually shortened) dystrophin molecule is synthesized; and Monaco et al. (1988) found that at the DNA level, the difference could often be shown to be whether the deletion causes a frameshift or otherwise interrupts the open reading frame. In BMD, the reading frame remains intact, although a coding segment of the gene has been lost. In the case of BMD, a shortened and only partially functional dystrophin is synthesized; in DMD, none is formed or the aborted molecule is degraded rapidly.
Testing the validity of the 'reading frame' theory in 258 independent deletions at the DMD locus, Koenig et al. (1989) found a correlation between phenotype and type of deletion that was in agreement with the theory in 92% of cases and was of diagnostic and prognostic significance. They predicted that many 'in-frame' deletions of the dystrophin gene are not detected because persons bearing them are either asymptomatic or exhibit atypical clinical features. Gillard et al. (1989) came to similar conclusions concerning the difference between in-frame and frameshift deletions. Beggs et al. (1990) described oligonucleotide primer sequences that can be used to amplify 8 exons plus the muscle promoter of the dystrophin gene in a single multiplex PCR. This and an existing primer set permitted detection of about 98% of deletions in patients with DMD or BMD. Palmucci et al. (1994) observed an unusually mild course of Becker muscular dystrophy in a 60-year-old farmer who was shown to have a 26% deletion of the DMD gene.
Davies et al. (1988) analyzed over 300 patients suffering from either Duchenne or Becker muscular dystrophy and concluded that severity of phenotype could not be correlated with the size of the deletion. One mildly affected BMD patient possessed a deletion of at least 110 kb including exons deleted in many DMD patients. Monaco et al. (1988) provided an explanation for the phenotypic differences between DMD and BMD: although no fundamental difference in the size of deletions appeared to be present in the 2 forms of disease, the deletions in DMD caused frameshifts while those in BMD did not. This finding is consistent with the fact that most patients with DMD are found to have no dystrophin protein in muscle, whereas patients with BMD are found to have an abnormally short variety (or, in 1 case, an abnormally long variety) of dystrophin. Presumably the dystrophin protein that is formed is functional, although not completely so.
Dubrovsky et al. (1995) reported a unique patient with both DMD and myotonic dystrophy (DM; 160900). DMD was diagnosed at age 6 years on the basis of the typical presentation of proximal muscle weakness, high creatine kinase, calf pseudohypertrophy, and a dystrophic muscle biopsy. There was no clinical or electrical evidence of myotonic dystrophy at that time. In a second biopsy at 18 years of age, dystrophin deficiency without a gene deletion mutation confirmed the diagnosis of isolated DMD. Myotonic dystrophy was diagnosed in the same patient at the age of 9 years on the basis of clinical and electrical myotonia, and a strong family history for the disorder. The diagnosis was confirmed by demonstrating a pathologic expansion of the CTG repeat in the mildly affected mother (160 repeats; normal, 27 repeats) and her more severely affected son (650 repeats) and daughter (650 repeats). The patient was still ambulatory beyond age 16. Dubrovsky et al. (1995) raised the possibility that myotonic dystrophy interfered to some extent with the progression of DMD. Other interpretations were considered. The 12% of dystrophin revertant fibers that was observed by immunohistochemistry could be sufficient to ameliorate typical DMD, or the patient might represent a somatic mosaic.
Kavaslar et al. (1995) described a 1-bp deletion in exon 6 of the DMD gene in a nondeleted patient with muscular dystrophy; whether Duchenne or Becker type was not stated. Either C640 or C641 was deleted. Kavaslar et al. (1995) stated that this was the twenty-fourth mutation identified involving only a single nucleotide, most of the previous ones having been substitutions. Only 5, including the one they reported, were deletion point mutations, and 3 of the 5 occurred in sequences in which a nucleotide was repeated once or twice.
At least 5 different promoters drive the transcription of tissue-specific dystrophin isoforms. Three promoters are located at the 5-prime end of the gene and give rise to 427-kD brain and muscle isoforms. Two other promoters drive the expression of alternate first exons spliced to distal parts of dystrophin sequence: these protein products are named (by their molecular weight) Dp116 and Dp71. The transcription of Dp116 is initiated at an alternate first exon located upstream to exon 56. Dp116 is exclusively expressed in Schwann cells as a thin rim of immunoreactivity located around the outside of the myelinated peripheral nerve fibers. Comi et al. (1995) described a patient showing a congenital form of muscle involvement, multiple dysmorphic features and severe mental retardation, associated with muscle dystrophin deficiency and absence of Dp116 in sural nerve. Sural nerve biopsies of 2 DMD patients expressing Dp116 were studied as controls. The patient, a 9-year-old boy, was born hypotonic into a family with no history of neuromuscular diseases. At 6 months of age he showed hypotonia, epicanthus, gothic palate, macroglossia, transverse palmar crease, and congenital hip dislocation. CK levels were high. EEG was dysrhythmic. At age 9 years, mental retardation was so striking that formal IQ assessment was impossible. Magnetic resonance imaging of brain showed foci of decreased signal intensity in periventricular white matter without gyral abnormalities. A mutation consisting of a G-to-A transition at the first nucleotide of intron 69 was demonstrated. Comi et al. (1995) commented on the clinical similarity to congenital Fukuyama muscular dystrophy (253800).
Todorova and Danieli (1997) reviewed 72 single-base mutations in the BMD gene from the point of view of possible origin and for consistency with the 'slipped-mispairing' and 'hypermutable CpG' models of mutagenesis. Moreover, repeated and symmetric elements, which could participate in the formation of secondary structures, were searched in each stretch of sequence that included a given mutant base. Unexpectedly, the frequency of CpG mutations was found to be less than that reported for other genes, whereas the frequency of transitions was found to be much higher than expected. Base substitutions in CpG dinucleotides that could be explained by methylation-mediated deamination were all C-to-T transitions. No G-to-A transitions in CpG dinucleotides were found. A sequence motif, which has been shown to act as an arrest site for polymerase alpha, occurred in association with more than 50% of single-base mutations. All the mutations but 1 could be explained by at least 2 mechanisms of mutagenesis. This would mean that, when a mutation might be produced independently by different mechanisms, a mutation would have a high probability at a given position. They concluded that the direct or inverted repeats seemed to play a major role.
In the course of characterizing the gene abnormality in patients from 2 unrelated Japanese families with X-linked dilated cardiomyopathy (CMD3B; 302045) and a deletion involving the muscle exon 1 of the DMD gene (Yoshida et al., 1993), Yoshida et al. (1998) found a unique insertion caused by integration of a human L1 element in the 5-prime untranslated region of muscle exon 1. The insertion was a 5-prime truncated form of human L1 inversely integrated into the DMD gene. It affected the transcription or stability of the muscle form of dystrophin transcripts but not that of the brain or Purkinje cell form, probably due to its unique site of integration. The 3 patients studied were first noted to have elevated serum creatine kinase levels (hyperCKemia) and electrocardiographic abnormalities at a school health screening. Two sibs had experienced exertional cramping myalgia since childhood. They showed no apparent muscular atrophy or weakness, but dilated cardiomyopathy was present. Patients 2 and 3 died of congestive heart failure at ages 18 and 14, respectively; the older brother of patient 3, who was not included in this study, also died of congestive heart failure at the age of 15 years. Patient 1, aged 25, was still alive at the time of report.
X-linked dilated cardiomyopathy is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLCM patients have been described with mutations that abolish dystrophin muscle isoform expression, but with increased expression of brain and cerebellar Purkinje isoforms of the gene exclusively in the skeletal muscle. Bastianutto et al. (2001) determined that 2 XLCM patients bore deletions that removed the muscle promoter and exon 1, but not the brain and cerebellar Purkinje promoters. The brain and cerebellar Purkinje promoters were found to be essentially inactive in muscle cell lines and primary cultures. Since dystrophin muscle enhancer-1 (DME1), a muscle-specific enhancer, is preserved in these patients, the authors tested its ability to upregulate the brain and cerebellar Purkinje promoters in muscle cells. Brain and cerebellar Purkinje promoter activity was significantly increased in the presence of DME1, and activation was observed exclusively in cells presenting a skeletal muscle phenotype versus cardiomyocytes. Bastianutto et al. (2001) suggested a role for DME1 in the induction of brain and cerebellar Purkinje isoform expression in the skeletal muscle of XLCM patients defective for muscle isoform expression.
The electroretinograms (ERGs) of patients with DMD and of an allelic variant of the mdx mouse are abnormal. Analysis of 5 allelic variants of the mdx mouse with mutations in the dystrophin gene showed that there is a correlation between the position of the mutation and the severity of the ERG abnormality. Three isoforms of the DMD protein are expressed in the retina: Dp427, Dp260, and Dp70. Using indirect immunofluorescence and isoform-specific antibodies on retinal sections from 3 allelic mdx mouse strains, Howard et al. (1998) examined the localization of each of the isoforms. They showed that Dp71 expression does not overlap with Dp427 and Dp260 expression at the outer plexiform layer (OPL). Instead, Dp71 is localized to the inner limiting membrane (ILM) and to retinal blood vessels. Moreover, Howard et al. (1998) showed that Dp260 and Dp71 differ structurally at their respective C-termini. In addition, they found that the proper localization of beta-dystroglycan (DAG1; 128239) is dependent on both Dp260 at the OPL and Dp71 expression at the ILM. Thus, Dp260 and Dp71 are nonredundant isoforms that are located at different sites within the retina, yet have a common interaction with beta-dystroglycan. These data suggested that both Dp71 and Dp260 contribute distinct but essential roles to retinal electrophysiology. (Howard et al. (1998) stated that the dystrophin gene is transcribed from at least 7 different promoters located in different regions of the gene. Four of these promoters are located within introns and encode short dystrophin isoforms, named according to their molecular weight.)
Studies in mice suggested that abnormalities of the electroretinogram occur predominantly with mutations involving the C-terminal dystrophin isoform, Dp260. Pillers et al. (1999) undertook a systematic evaluation of DMD/BMD patients to determine whether the position-specific effects of mutations noted in the mouse are present in man. In man, they found a wider variation of DMD defects correlated with reductions in the b-wave amplitude. Individuals with normal ERGs had mutations predominantly located 5-prime of the transcript initiation site of Dp260; among these patients, 46% had abnormal ERGs, as opposed to 94% with more distal mutations. The human genotype/phenotype correlations are consistent with a role for Dp260 in normal retinal electrophysiology and may also reflect the expression of other C-terminal dystrophin isoforms and their contributions to retinal signal transmission.
Moizard et al. (2000) performed mutation analysis of the Dp71 transcript in 12 DMD patients who were severely, mildly, or not retarded and had no detectable deletion or duplication. They detected 5 point mutations causing premature translation termination of Dp71. All of the mutations were found among the more severely mentally retarded patients of this group; see 300377.0076.
Ginjaar et al. (2000) studied an X-linked muscular dystrophy family in which 3 males had very different phenotypes that appeared to be related to the level of skipping of exon 29 in the DMD gene; see 300377.0077.
Greener et al. (2002) studied the evolutionary conservation of the 3-prime-UTR of the DMD gene, previously described for the chicken ortholog, by isolating the corresponding sequences from the amphibian Xenopus laevis and the dogfish Scyliorhinus canicula, a species that diverged from human more than 420 million years ago. The Xenopus sequence showed high continuous similarity to the 'Lemaire A' region of human and chicken dystrophin 3-prime-UTRs, whereas the dogfish sequence contained homologous sequences at both Lemaire A and D regions. The function of these highly conserved regions remained unexplained. The authors also described the precise nature of a mutation resulting in the loss of exon 79 and 3-prime-UTR from the dystrophin gene in 3 brothers with Becker muscular dystrophy (BMD; 300376). Very few mutations involving the 3-prime-UTR of the dystrophin gene had been described, a fact that might be explained by the pragmatic decision not to include this region in most screening protocols but, given their high level of conservation, Greener et al. (2002) suggested that point mutations affecting Lemaire A or D regions might result in a BMD phenotype.
Approximately 80% of Becker patients have deletions in the dystrophin gene, most of which correspond to an exact multiple of codons so that some partially functional dystrophin of altered sequence is produced. Tuffery-Giraud et al. (2005) reported 5 splice site mutations in the DMD gene in 5 patients with Becker muscular dystrophy. In 2 cases, the milder phenotype was due to exon skipping leading to an in-frame deletion. In 2 other cases, intronic mutations resulted in complex splicing changes, but with some residual normal transcripts. The last case resulted in a truncated transcript missing only part of the C terminus of the protein, suggesting that this region is not critical for dystrophin function. Tuffery-Giraud et al. (2005) noted that the characterization of DMD mRNA changes may aid in therapeutic strategies involving the induction of exon-skipping events in order to restore the reading frame (see Goyenvalle et al., 2004).
Gurvich et al. (2008) noted that some splice site mutations in the DMD gene (see 300377.0080) can result in inclusion of intronic sequences in the transcript, referred to as 'pseudoexons.' The amount of pseudoexon-containing transcript relative to wildtype transcript is dependent on the efficiency of the novel splice site created by the mutation. In muscle from a BMD patient, a significant level of wildtype transcript was present (13% of that found in control muscle), whereas in muscle from a DMD patient, no wildtype transcript was detected, suggesting that the difference in disease severity between BMD and DMD could be explained by differential efficiency in the function of the mutation-induced splice site. Studies in mutant muscle cell cultures showed that treatment with antisense oligonucleotides against pseudoexon sequences could result in expression of full-length wildtype dystrophin.
Daoud et al. (2009) reported a comparison of clinical, cognitive, molecular, and expression data in 81 patients with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) bearing mutations predicted to affect either all dystrophin products (including Dp71) or all dystrophin products except Dp71. Consistent data were presented defining the molecular basis underlying mental retardation in DMD; BMD patients with mental retardation were shown to have mutations that significantly affected Dp71 expression or with mutations located in exons 75 and 76. Mutations upstream to exon 62 (with DMD phenotype) which were predicted to lead to a loss-of-function of all dystrophin products (except Dp71 isoform) were predominantly associated with normal or borderline cognitive performance. Daoud et al. (2009) concluded that the reliable genotype/phenotype correlations, in combination with Dp71 mRNA and protein expression studies, strongly indicate that loss-of-function of all dystrophin products is systematically associated with a severe form of mental retardation, and that Dp71 deficit is a factor that contributes to the severity of mental retardation and may account for a 2 standard deviation decrease in IQ.
Gurvich et al. (2009) identified a truncating mutation in exon 1 of the DMD gene (W3X; 300377.0086) that was associated with a mild Becker phenotype. Studies in reporter constructs, which encompassed exons 1 to 9 of the muscle isoform of DMD, identified 2 alternative translation initiation sites within exon 6 that resulted in the production of a shorter 60-kD protein that presumably retained enough residual activity to ameliorate the more severe phenotype expected with such a mutation. The findings suggested that truncating mutations within the first 2 exons of the DMD gene may result in the utilization of downstream translational start sites, that these aberrant transcripts somehow avoid nonsense-mediated decay, and that the first 5 exons of DMD are not necessary to maintain significant protein function.
Carsana et al. (2005) evaluated genotype/phenotype associations in 108 unrelated patients with BMD and DMD. In-frame deletions of the hinge III region in the distal rod domain of the DMD gene correlated to a milder phenotype in BMD compared to shorter deletions that do not include this region. Immunohistochemical studies in muscle tissue from 5 patients with BMD and deletions in the hinge III region showed a milder pattern compared to 5 patients with BMD and deletions outside the hinge III region.
Wang et al. (2018) examined genotype/phenotype correlations in patients from the Duchenne Registry database who had mutations in the DMD gene that were amenable to exon 44 or exon 8 skipping. Patients with these mutations had a later age of loss of ambulation compared to patients with mutations amenable to skipping of other exons in the DMD gene. Further analysis of specific mutations demonstrated that deletion of exon 45 was associated with later loss of ambulation compared to other mutations that were amenable to skipping of exon 44, and deletion of exons 3-7 showed later loss of ambulation compared to other exon 8 skippable mutations. In cultured myotubes derived from fibroblasts of 3 patients with a deletion of exon 45, the basal levels of exon 44 skipping were enriched to 8 to 90%. Similarly, exon 8 skipping was enriched in myotubes derived from fibroblasts of a patient with an exon 5-7 deletion. Wang et al. (2018) hypothesized that the basal levels of exon skipping may explain the relatively milder clinical disease associated with these genotypes.
Zambon et al. (2022) analyzed molecular and clinical data from the United Dystrophinopathy Project and Italian DMD network databases. Sixty-six patients with a duplication of exon 2 of the DMD gene were identified. Among these patients, 61% had DMD, 9% had intermediate muscular dystrophy (IMD), and 30% had BMD. The age of loss of ambulation in patients with DMD and exon 2 duplications occurred later than in patients with other mutations. There was also a suggestion that DMD patients with exon 2 duplications had a delayed decline in forced vital capacity compared to patients with DMD and other mutations.
Sicinski et al. (1989) used PCR to demonstrate the first point mutation in the dystrophin gene. In the mdx mouse, they found that cytosine replaced thymine at nucleotide position 3185, resulting in a termination codon (TAA) in place of a glutamine codon (CAA). The mutation in an exon to a stop codon resulted in premature termination of translation of 27% of the length of the dystrophin polypeptide. Because of the high frequency of glutamine codons in the dystrophin gene (and other triplets that could mutate to a stop codon), a mechanism for high frequency of point mutations is provided.
Dickson et al. (1988) found distinctive mRNA isoforms of dystrophin in embryonic mouse muscle. They suggested that these distinct mRNAs are most likely generated by a selection of alternative transcriptional start sites or RNA processing pathways. Lee et al. (1991) synthesized a 14-kb full-length cDNA for mouse muscle dystrophin mRNA and demonstrated its expression in COS cells. The recombinant dystrophin was indistinguishable from mouse muscle dystrophin by Western blot analysis with anti-dystrophin antibodies and was shown by an immunofluorescent technique to be localized to the cytoplasmic face of the cell membrane, its normal position. Lee et al. (1991) suggested that the work opens up the possibility for gene therapy studies. Bittner et al. (1994) detected high titers of antibody specific for dystrophin in the sera of mdx mice who had received dystrophin-containing muscle grafts from coisogenic normal mice. The dystrophin-containing muscle grafts were not rejected even in the presence of high titer antibodies. Bittner et al. (1994) suggested that this transplantation approach may serve as a model for immunologic identification of missing proteins in other diseases where null mutant animal models exist. McArdle et al. (1994) used mdx mice to test the 'membrane permeability' hypothesis of Duchenne muscular dystrophy first put forward by Lewis Rowland (Rowland, 1980). Permeability of the skeletal muscle membranes to either a vital stain (procion orange) or extracellular calcium-45 was present in necrotic, but not prenecrotic, fibers. There was no evidence for an increase in muscle plasma membrane permeability as a primary pathogenic effect of a lack of dystrophin. In contrast to the failure of regeneration found in DMD patients, Itagaki et al. (1995) found no difference in regenerative capacity of mdx mouse muscles after repeated applications of bupivacaine, a myonecrotic agent. This is in keeping with normal life span without distinct muscle weakness in mdx mice. Hagiwara et al. (1995) transplanted C2 myoblast into the tibialis anterior of mdx nude mice and demonstrated the formation of a small number of mosaic host donor muscle fibers.
Contrary to the location of the dystrophin gene on the X chromosome in man and all other eutherian mammals studied, the gene maps to an autosomal microchromosome in the chicken (Gallus domesticus) (Dominguez-Steglich et al., 1990).
The prospects of gene therapy for muscular degenerative diseases such as DMD were brightened by the demonstration by Stratford-Perricaudet et al. (1992) that efficient, long-term in vivo gene transfer throughout mouse skeletal and cardiac muscles occurred after intravenous administration of a recombinant adenovirus. Cox et al. (1993) explored the feasibility of gene therapy for DMD by examining the potential of a full-length dystrophin transgene to correct the severe abnormalities of the diaphragm muscle that occur in the mdx mouse. They found, indeed, that the abnormalities could be prevented in the transgenic mdx mouse; furthermore, overexpression of dystrophin prevented the abnormal mechanical properties associated with dystrophic muscle without causing deleterious side effects. Expression levels of dystrophin 50 times the normal were tolerated without adverse toxic effects.
Cooper et al. (1988) demonstrated that muscular dystrophy in the golden retriever dog is X-linked. They suggested, furthermore, that the disorder may be homologous to human BMD. The G-banded karyotype of the dog was illustrated. No chromosomal abnormalities were visualized in a carrier female or an affected male. The molecular studies by Valentine et al. (1992) showed a defect in dystrophin, thus establishing the authenticity of the canine model. Sharp et al. (1992) described a molecular defect in X-linked muscular dystrophy of the golden retriever dog (GRMD). Analysis of the DMD gene in the GRMD dogs failed to demonstrate detectable loss of exons; however, a change from AG to GG in the 3-prime splice-acceptor site of intron 6 resulted in skipping of exon 7 in the processed mRNA. Sharp et al. (1992) stated that this was the first example of dystrophin deficiency caused by a splice site mutation.
Vieira et al. (2015) observed 2 GRMD 'escaper' dogs that remained fully ambulatory with normal lifespans. By genomewide mapping and gene expression analysis, they found that expression of Jag1 (601920) mRNA was 2-times higher in escaper GRMD muscle compared with wildtype and severely affected GRMD muscle. Sequence analysis revealed a heterozygous G-T change in the promoter region of the Jag1 gene in both escaper dogs that introduced a myogenin (MYOG; 159980) consensus binding motif. This Jag1 variant was absent in wildtype and severely affected GRMD dogs. EMSA and reporter gene analysis showed Myog binding and elevated reporter expression from the escaper Jag1 promoter but not the wildtype promoter. Introduction of escaper Jag1 rescued the muscle lethality phenotype of the zebrafish sapje model of DMD. Muscle cells from GRMD escaper dogs showed the typical dystrophic features of degeneration and regeneration, but escaper myogenic cells in culture divided significantly faster than those from severely affected dogs. Moreover, Vieira et al. (2015) found elevated Jag1 expression in mouse tibialis anterior muscle following cardiotoxin-induced injury and following myoblast differentiation in vitro. They concluded that elevated Jag1-dependent Notch signaling enhances the proliferative capacity of activated muscle satellite cells in escaper GRMD dogs.
Tinsley et al. (1996) pointed out that replacement of the missing protein, dystrophin, using myoblast transfer in humans or viral/liposomal delivery in the mouse DMD model is insufficient and short-lived. An alternative approach to treatment would be to upregulate the closely related protein, utrophin (128240), which might be able to compensate for the dystrophin deficiency in all relevant muscles. As a first step to this approach, Tinsley et al. (1996) expressed a utrophin transgene at high levels in the dystrophin-deficient mdx mouse. The results indicated that high expression of the utrophin transgene in skeletal and diaphragm muscle can markedly reduce the dystrophic pathology. These data suggested to the authors that systemic upregulation of utrophin in DMD patients may lead to the development of an effective treatment for this devastating disorder.
A significant number of the mutations in the DMD gene leading to muscular dystrophy are premature stop codons. On the basis of the observation that aminoglycoside treatment can suppress stop codons in cultured cells, Barton-Davis et al. (1999) tested the effect of gentamicin on cultured muscle cells from the mdx mouse, an animal model for DMD that possesses a premature stop codon in the dystrophin gene. Exposure of mdx myotubes to gentamicin led to the expression and localization of dystrophin to the cell membrane. Studying the effects of differing doses of gentamicin, Barton-Davis et al. (1999) identified a treatment regimen that resulted in the presence of dystrophin in the cell membrane in all striated muscles examined and that provided functional protection against muscular injury. This appeared to be the first demonstration that aminoglycosides can suppress stop codons not only in vitro but also in vivo. The result raises the possibility of a novel treatment program not only for muscular dystrophy but also for other diseases caused by premature stop codon mutations. They estimated that this treatment could prove effective in up to 15% of patients with DMD.
Mankin and Liebman (1999) reviewed the basis of treating genetic diseases with aminoglycosides. They pointed out that Burke and Mogg (1985) had suggested the use of aminoglycosides. Using cultured mammalian cells, Burke and Mogg (1985) showed that aminoglycoside antibiotics could partially restore the synthesis of a full-sized protein from a mutant gene with a premature UAG mutation. While the anticodons of aminoacyl transfer RNAs (tRNAs) recognize sense codons, leading to the incorporation of a specific amino acid during protein synthesis, there are normally no tRNAs with anticodons that precisely match any of the 3 nonsense (stop) codons: UAA, UAG, and UGA. Rather, these codons are recognized by proteins that promote the release of the completed polypeptide chain. When a nonsense codon results from mutation in a structural gene, the protein product is incomplete at the time the polypeptide chain is released. Mankin and Liebman (1999) reviewed the 'downside' of the approach. The activity of the protein containing an altered amino acid in place of the premature stop, the amount of the protein required to carry out its cellular function and its stability would clearly impose limitations. Moreover, the increased frequency of translation errors would result in the production of aberrant proteins, which, together with the other known side effects of gentamicin (and yet unknown consequences of the long-term use of the drug), would make it tricky to find effective treatment regimens.
Gussoni et al. (1999) reported the results of bone marrow transplantation in the mdx mouse. Intravenous injection of either normal hematopoietic stem cells or a novel population of muscle-derived stem cells into irradiated animals resulted in the reconstitution of the hematopoietic compartment of the transplanted recipients, the incorporation of donor-derived nuclei into muscle, and the partial restoration of dystrophin expression in the affected muscle. Gussoni et al. (1999) concluded that the most practical observation in their studies was that bone marrow or muscle stem cells appear to provide a means for systemic rather than local repair of muscle as a consequence of the delivery of the cells throughout the vascular system. In addition, the experiments provided evidence that hematopoietic stem cells with the capacity for the complete reconstitution of lethally irradiated recipients have the potential to differentiate into muscle.
To identify potential nonmechanical roles of dystrophin, Rafael et al. (2000) tested the ability of various truncated dystrophin transgenes to prevent any of the skeletal muscle abnormalities associated with the double knockout mouse deficient for both dystrophin and utrophin. Restoration of the dystrophin-associated protein complex (DAPC) with Dp71 did not prevent the structural abnormalities of the postsynaptic membrane or the abnormal oxidative properties of utrophin/dystrophin-deficient muscle. In contrast, a dystrophin protein lacking the cysteine-rich domain, which is unable to prevent dystrophy in the mdx mouse, was able to ameliorate these abnormalities in utrophin/dystrophin-deficient mice. The authors concluded that in addition to a mechanical role, dystrophin and utrophin are able to alter both structural and biochemical properties of skeletal muscle.
Dystrophin-deficient muscles show large reductions in expression of nitric oxide synthase (NOS1; 163731), which suggests that NO deficiency may influence the dystrophic pathology. Because NO can function as an antiinflammatory and cytoprotective molecule, Wehling et al. (2001) proposed that the loss of NOS from dystrophic muscle exacerbates muscle inflammation and fiber damage by inflammatory cells. Analysis of transgenic mdx mice that were null mutants for dystrophin, but expressed normal levels of NO in muscle, showed that the normalization of NO production caused large reductions in macrophage concentrations in the mdx muscle. Expression of the NOS transgene in mdx muscle also prevented most of the muscle membrane injury that was detectable in vivo, and resulted in large decreases in serum creatine kinase concentrations. The data also showed that mdx muscle macrophages are cytolytic at concentrations that occur in dystrophic, NOS-deficient muscle, but are not cytolytic at concentrations that occur in dystrophic mice that express the NOS transgene in muscle. The data showed, furthermore, that depletion of macrophages by antibody in mdx mice causes significant reductions in muscle membrane injury.
'Revertant fibers' are muscle fibers containing a low percentage of dystrophin-positive cells. These are present in the dystrophin-deficient mdx mouse, and are believed to result from alternative splicing or second mutation events that bypass the mutation and restore an open reading frame. Crawford et al. (2001) found that newborn transgenic mice displayed approximately the same number of revertant fibers as newborn mdx mice, indicating that expression of a functional dystrophin does not suppress the initiation of revertant fiber formation. However, when the transgene encoded a functional dystrophin, revertant fibers were not detected in adult or old mdx mice. In contrast, adult transgenic mice expressing a nonfunctional dystrophin accumulated increasing numbers of revertant fibers, similar to mdx mice, suggesting that positive selection is required for the persistence of revertant fibers. The authors further provided evidence that the loss of revertant dystrophin in transgenic mdx muscle fibers overexpressing a functional dystrophin resulted from displacement of the revertant protein by the transgene-encoded dystrophin.
With a view to developing gene therapy for DMD with the adeno-associated virus vector, which can accommodate a gene of only limited length, Sakamoto et al. (2002) generated a series of rod-truncated microdystrophin cDNAs and used them, driven by a CAG promoter, to produce transgenic mdx mice. The authors showed that all 3 microdystrophins localized at the sarcolemma together with the expression of dystrophin-associated proteins. One of them, containing 4 rod repeats, greatly improved dystrophic phenotypes of mdx mice, and contractile force of the diaphragm in particular was restored to normal. The second of them, containing 3 rod repeats, resulted in modest amelioration of the dystrophic pathology, but a third, containing 1 rod repeat, showed no improvement.
Harper et al. (2002) performed a detailed functional analysis of dystrophin structural domains and showed that multiple regions of the protein can be deleted in various combinations to generate highly functional mini- and micro-dystrophins. Studies in transgenic mdx mice, a model for DMD, revealed that a wide variety of functional characteristics of dystrophy are prevented by some of these truncated dystrophins. Muscles expressing the smallest dystrophins were fully protected against damage caused by muscle activity and were not morphologically different from normal muscle. Moreover, injection of adeno-associated viruses carrying micro-dystrophins into dystrophic muscles of immunocompetent mdx mice resulted in a striking reversal of histopathologic features of the disease. Harper et al. (2002) concluded that the dystrophic pathology can be both prevented and reversed by gene therapy using micro-dystrophins.
Previous demonstrations that the enteroviral protease 2A cleaves dystrophin (Badorff et al., 1999; Badorff et al., 2000; Lee et al., 2000) led Xiong et al. (2002) to hypothesize that dystrophin deficiency would predispose to enterovirus-induced cardiomyopathy. In dystrophin-deficient mice infected with enterovirus, Xiong et al. (2002) observed more severe cardiomyopathy, worsening over time, and greater viral replication than in infected wildtype mice. The difference appeared to be a result of more efficient release of the virus from dystrophin-deficient myocytes. In addition, Xiong et al. (2002) found that expression of wildtype dystrophin in cultured cells decreased the cytopathic effect of enteroviral infection and the release of virus from the cell. They also found that expression of a cleavage-resistant mutant dystrophin further inhibited the virally mediated cytopathic effect and viral release. The results indicated that viral infection can influence the severity and penetrance of the cardiomyopathy that occurs in the hearts of dystrophin-deficient individuals.
Using DNA microarray, Porter et al. (2002) established a molecular signature of dystrophinopathy in the mdx mouse. In leg muscle, 242 differentially expressed genes were identified. Data provided evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Upregulation of secreted phosphoprotein 1 (SPP1; 166490) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were upregulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggested that collagen regulation at posttranscriptional stages may mediate extensive fibrosis in DMD.
Fabb et al. (2002) designed an adeno-associated viral (AAV) vector containing a micro-dystrophin cDNA gene construct that is less than 3.8 kb. This construct, driven by a CMV promoter, was introduced into the skeletal muscle of 12-day-old nude/mdx mice, resulting in specific sarcolemmal expression of micro-dystrophin in more than 50% of myofibers up to 20 weeks of age, and effective restoration of the DAP complex components. Additionally, evaluation of central nucleation indicated a significant inhibition of degenerative dystrophic muscle pathology.
Warner et al. (2002) constructed transgenic mice expressing Dp260 in skeletal muscle. Dp260 lacks the N-terminal domain and a significant portion of the rod domain, but retains the rod domain actin-binding domain. Expression of the abbreviated protein restored a stable association between costameric actin and the sarcolemma, fostered assembly of the dystrophin-glycoprotein complex, and significantly slowed the progression of the dystrophy in the dystrophin-deficient mdx mouse. Although Dp260 muscles showed normal resistance to contraction-induced injury, these muscles showed dramatic reductions in force generation, similar to mdx muscles. Morphologically, Dp260 muscles displayed reduced amounts of inflammation and fibrosis, but still showed a significant, albeit reduced, amount of degeneration/regeneration. The authors concluded that data protection from contraction-induced injury may dramatically ameliorate, but not completely halt, the dystrophic process. They speculated that a nonmechanical defect, attributed to the loss of the N terminus of dystrophin, is likely responsible for the residual dystrophy observed.
Bogdanovich et al. (2002) blocked endogenous myostatin (MSTN; 601788) in mdx mice by intraperitoneal injections of blocking antibodies for 3 months and found increase in body weight, muscle mass, muscle size, and absolute muscle strength along with a significant decrease in muscle degeneration and concentrations of serum creatine kinase. Bogdanovich et al. (2002) concluded that myostatin blockade provides a novel, pharmacologic strategy for treatment of diseases associated with muscle wasting such as DMD, and circumvents the major problems associated with conventional gene therapy in these disorders.
To explore the hypothesis that the dystrophin rod domain acts as a spacer region, Harper et al. (2002) expressed a chimeric microdystrophin transgene containing the 4-repeat rod domain of alpha-actinin-2 (102573) in mdx mice. The chimeric transgene was incapable of correcting the morphologic pathology of the mdx mouse, but still functioned to assemble the dystrophin-glycoprotein complex at the membrane and provided some protection from contraction-induced injury. The authors concluded that different spectrin-like repeats are not equivalent, and suggested that the dystrophin rod domain is not merely a spacer but likely contributes an important mechanical role to overall dystrophin function.
Most mutations in the dystrophin gene occur in the region encoding the spectrin-like central rod domain, which is largely dispensable. Thus, splicing around mutations can generate a shortened but in-frame transcript, permitting translation of a partially functional dystrophin protein. Lu et al. (2003) tested this idea in vivo in the mdx dystrophic mouse by combining a potent transfection protocol with an antisense oligoribonucleotide designed to promote skipping of the mutated exon 23. The treated mice showed persistent production of dystrophin at normal levels in large numbers of muscle fibers and showed functional improvement of the treated muscle. Repeated administration enhanced dystrophin expression without eliciting immune responses. The data established the practicality of an approach that is applicable, in principle, to a majority of cases of severe dystrophinopathy.
Bertoni et al. (2003) tested the ability of chimeric RNA/DNA oligonucleotides (chimeraplasts) to alter key bases in specific splice sequences in the dystrophin gene to induce exon skipping. In mdx mouse cells, chimeraplast-mediated base conversion in the intron 22/exon 23 splice junction induced alternative splicing and the production of in-frame transcripts. Multiple alternative transcripts were induced, several of which were predicted to produce in-frame dystrophin transcripts with internal deletions. Multiple forms of dystrophin protein were observed by Western blot analysis, and the functionality of the products was demonstrated by the restoration of expression and localization of alpha-dystroglycan (DAG1; 128239) in differentiated cells. Bertoni et al. (2003) concluded that chimeraplasts can induce exon skipping by altering splice site sequences at the genomic level.
The abnormal retinal neurotransmission observed in patients with Duchenne muscular dystrophy and in some genotypes of mice lacking dystrophin has been attributed to altered expression of short products of the dystrophin gene. Dalloz et al. (2003) investigated the potential role of Dp71, the most abundant C-terminal dystrophin gene product, in retinal electrophysiology. Comparison of the scotopic ERGs between Dp71-null mice and wildtype littermates revealed a normal ERG in Dp71-null mice with no significant changes of the b-wave amplitude and kinetics. Analysis of Dmd gene products, utrophin (UTRN; 128240), and dystrophin-associated proteins (DAPs) showed that Dp71 and utrophin were localized around the blood vessels, in the ganglion cell layer (GCL), and at the inner limiting membrane (ILM). Dp71 deficiency was accompanied by an increased level of utrophin and decreased level of beta-dystroglycan (DAG1; 128239) localized in the ILM, without any apparent effect on the other DAPs. Dp71 deficiency was also associated with an impaired clustering of 2 Muller glial cell proteins: the inwardly rectifying potassium channel Kir4.1 (KCNJ10; 602208) and the water pore aquaporin-4 (AQP4; 600308). Immunostaining of both proteins decreased around blood vessels and in the ILM of Dp71-null mice, suggesting that Dp71 plays a role in the clustering and/or stabilization of the 2 proteins.
Porter et al. (2003) used temporal gene expression profiling to identify and correlate diverse transcriptional patterns in dystrophin-deficient mdx mice. Although 719 transcripts were differentially expressed at 1 or more ages in leg muscle, only 56 genes were altered in the spared extraocular muscles (EOM). Contrasting molecular signatures of affected versus spared muscles provided evidence that the absence of dystrophin alone was necessary but not sufficient to cause the patterned fibrosis, inflammation, and failure of muscle regeneration characteristic of dystrophinopathy. An aggregate disease load index (DLI) highlighted the divergent responses of EOM and leg muscle groups. Cellular process-specific DLIs in leg muscle identified positively correlated temporal expression profiles for some gene classes, and the independence of others, that are linked to major disease components. Porter et al. (2004) characterized temporal expression profiles of the diaphragm in mdx mice between postnatal days 7 and 112 and contrasted these data with hindlimb muscle findings reported by Porter et al. (2003). The 2 muscle groups principally differed in expression levels of differentially regulated genes, as opposed to nonconserved induced/repressed transcripts defining fundamentally distinct mechanisms. A postnatal divergence of the 2 wildtype muscle group expression profiles was identified that temporally correlated with the onset and progression of the dystrophic process. Porter et al. (2004) hypothesized that conserved disease mechanisms interacting with baseline differences in muscle group-specific transcriptomes may underlie their differential response to DMD.
ADAM12 (602714) is a disintegrin and metalloprotease demonstrated to prevent muscle cell necrosis in the mdx mouse (Kronqvist et al., 2002). Moghadaszadeh et al. (2003) found that transgenic mice overexpressing ADAM12 exhibited only mild myopathic changes and accelerated regeneration following acute injury. Only small changes in gene expression profiles were found between mdx/ADAM12 transgenic mice and mdx mice, suggesting that significant changes in mdx/ADAM12 muscle might occur posttranscriptionally. By immunostaining and immunoblotting, Moghadaszadeh et al. (2003) detected a 2-fold increase in expression and extrasynaptic localization of alpha-7B integrin (ITGA7; 600536) and utrophin (128240), the functional homolog of dystrophin. Expression of dystrophin-associated glycoproteins was also increased.
Using TO-2 hamsters, Toyo-Oka et al. (2004) demonstrated age-dependent cleavage and translocation of myocardial dystrophin from the sarcolemma to the myoplasm, increased sarcolemmal permeability in situ, and a correlation between the loss of dystrophin and hemodynamic indices, and between the amount of dystrophin and the survival rate. Transfer of the missing delta-sarcoglycan gene to degrading cardiomyocytes in vivo ameliorated all of the pathologic features. The authors demonstrated dystrophin disruption in rats with acute heart failure from isoproterenol toxicity or with chronic heart failure after coronary ligation. They also found dystrophin cleavage in human hearts from patients with dilated cardiomyopathy of unidentified etiology. Toyo-Oka et al. (2004) proposed a common mechanism for heart failure involving sarcolemmal instability, dystrophin cleavage, and translocation of dystrophin from the sarcolemma to the myoplasm, irrespective of whether the disease is acute or chronic, or hereditary or acquired in origin.
Goyenvalle et al. (2004) achieved persistent exon skipping that removed the mutated exon on the dystrophin mRNA of the mdx mouse by single administration of an adeno-associated virus (AAV) vector expressing antisense sequences linked to a modified U7 small nuclear RNA (RNU7-1; 617876). Goyenvalle et al. (2004) reported the sustained production of functional dystrophin at physiologic levels in entire groups of muscles and the correction of the muscular dystrophy.
Yue et al. (2004) generated female heterozygous mdx mice that persistently expressed the full-length dystrophin gene in 50% of cardiomyocytes. Heart function of mdx mice was normal in the absence of external stress. Using beta-isoproterenol challenge in 3-month-old mice, they showed that cardiomyocyte sarcolemma integrity was significantly impaired in mdx but not in heterozygous mdx and C57BL/10 mice. In vivo closed-chest hemodynamic assays revealed normal left ventricular function in beta-isoproterenol-stimulated heterozygous mdx mice. The nonuniform dystrophin expression pattern in heterozygous mdx mice resembled the pattern seen in viral gene transfer studies. Yue et al. (2004) concluded that gene therapy correction in 50% of heart cells may be sufficient to treat cardiomyopathy in mdx mice.
ARC (NOL3; 605235) is an abundant protein in human muscle that can inhibit both hypoxia and CASP8 (601763)-induced apoptosis, as well as protect cells from oxidative stress. To investigate a potential role for ARC in protecting muscle fiber from dystrophic breakdown, Abmayr et al. (2004) cloned and characterized murine Arc and studied its expression in normal and dystrophic mouse muscle. Arc expression levels were normal in mdx mice, and overexpression of Arc in mdx mice failed to alleviate the dystrophic pathology in skeletal muscles, suggesting that misregulation of the molecular pathways regulated by Arc does not significantly contribute to myofiber death.
Some patients with dystrophin mutations suffer from X-linked dilated cardiomyopathy (CMD3B; 302045) but are devoid of skeletal muscle myopathy. The absence of skeletal muscle symptoms has been attributed to expression of the brain and cerebellar Purkinje (CP) isoforms of dystrophin in skeletal, but not cardiac, muscles of CMD3B patients. Brain and cerebellar Purkinje dystrophin promoter upregulation has been attributed to activity of the dystrophin muscle enhancer-1 (DME1). De Repentigny et al. (2004) demonstrated that the mouse dystrophin CP promoter drove expression of a reporter gene specifically to the cerebellar Purkinje cell layer, but not to skeletal or cardiac muscle of transgenic mice. When the mouse counterpart of DME1 was present in the transgene construct, the dystrophin CP promoter was activated in skeletal muscle, but not in cardiac muscle.
Yasuda et al. (2005) showed that intact, isolated dystrophin-deficient cardiac myocytes have reduced compliance and increased susceptibility to stretch-mediated calcium overload, leading to cell contracture and death, and that application of the membrane sealant poloxamer-188 corrects these defects in vitro. In vivo administration of poloxamer-188 to dystrophic mice instantly improved ventricular geometry and blocked the development of acute cardiac failure during a dobutamine-mediated stress protocol. Yasuda et al. (2005) suggested that once issues relating to optimal dosing and long-term effects of poloxamer-188 in humans have been resolved, chemical-based membrane sealants could represent a therapeutic approach for preventing or reversing the progression of cardiomyopathy and heart failure in muscular dystrophy.
Both dystrophin and alpha-7/beta-1 (ITGB1; 135630) integrin have critical roles in the maintenance of muscle integrity by providing mechanical links between muscle fibers and the basement membrane. Guo et al. (2006) created Dmd/Itga7 double-knockout mice (DKO), which appeared normal at birth, but died within the first month of life with severe muscular dystrophy, endomysial fibrosis, and ectopic calcification. Progressive muscle wasting in the DKO mice was likely due to inadequate muscle regeneration, and the premature death appeared to be due to cardiac and/or respiratory failure.
Bellinger et al. (2009) found that the calcium channel Ryr1 (180901) in skeletal muscle from mdx mice showed increased inducible nitric oxide (NOS2A; 163730)-mediated S-nitrosylation of cysteine residues, which depleted the channel complex of calstabin-1 (FKBP12; 186945). This resulted in leaky channels with increased calcium flux. These changes were age-dependent and coincided with dystrophic changes in muscle. Prevention of calstabin-1 depletion from Ryr1 with S107, a compound that binds the Ryr1 channel and enhances binding affinity, inhibited sarcoplasmic reticulum calcium leak, reduced biochemical and histologic evidence of muscle damage, improved muscle function, and increased exercise performance in mdx mice. Bellinger et al. (2009) proposed that the increased calcium flux via a defective Ryr1 channel contributes to muscle weakness and degeneration in DMD by increasing calcium-activated proteases.
Li et al. (2009) generated delta-sarcoglycan (SGCD; 601411)/dystrophin double-knockout mice (delta-Dko) in which residual sarcoglycans were completely eliminated from the sarcolemma. Utrophin (UTRN; 128240) levels were increased in these mice but did not mitigate disease. The clinical manifestation of delta-Dko mice was worse than that of mdx mice. They showed characteristic dystrophic signs, body emaciation, macrophage infiltration, decreased life span, less absolute muscle force, and greater susceptibility to contraction-induced injury. Li et al. (2009) suggested that subphysiologic sarcoglycan expression may play a role in ameliorating muscle disease in mdx mice.
Li et al. (2009) investigated the role and the mechanisms by which increased levels of matrix metalloproteinase-9 (MMP9; 120361) protein cause myopathy in dystrophin-deficient mdx mice. MMP9 levels but not tissue inhibitor of MMPs were drastically increased in skeletal muscle of mdx mice. Infiltrating macrophages also contributed to the elevated levels of MMP9 in dystrophic muscle. In vivo administration of NFKB-inhibitory peptide NBD blocked the expression of MMP9 in dystrophic muscle of mdx mice. Deletion of the Mmp9 gene in mdx mice improved skeletal muscle structure and functions and reduced muscle injury, inflammation, and fiber necrosis. Inhibition of MMP9 increased the levels of cytoskeletal protein beta-dystroglycan and Nos1 and reduced the amounts of caveolin-3 (CAV3; 601253) and transforming growth factor-beta (TGFB1; 190180) in myofibers of mdx mice. Genetic ablation of MMP9 significantly augmented the skeletal muscle regeneration in mdx mice. Pharmacologic inhibition of MMP9 activity also ameliorated skeletal muscle pathogenesis and enhanced myofiber regeneration in mdx mice.
Wehling-Henricks et al. (2009) tested whether the loss of neuronal nitric oxide synthase, nNOS (NOS1; 163731), contributes to the increased fatigability of mdx mice. The expression of a muscle-specific nNOS transgene increased the endurance of mdx mice and enhanced glycogen metabolism during treadmill running, but did not affect vascular perfusion of muscles. The specific activity of phosphofructokinase (PFK; 610681), the rate-limiting enzyme in glycolysis, was positively affected by nNOS in muscle; PFK-specific activity was significantly reduced in mdx muscles and the muscles of nNOS-null mutants, but significantly increased in nNOS transgenic muscles and muscles from mdx mice that expressed the nNOS transgene. PFK activity measured under allosteric conditions was significantly increased by nNOS, but unaffected by endothelial NOS or inducible NOS. The specific domain of nNOS that positively regulates PFK activity was assayed by cloning and expressing different domains of nNOS and assaying their effects on PFK activity. This approach yielded a polypeptide that included the flavin adenine dinucleotide (FAD)-binding domain of nNOS as the region of the molecule that promotes PFK activity. A 36-amino acid peptide in the FAD-binding domain was identified in which most of the positive allosteric activity of nNOS for PFK resides. Wehling-Henricks et al. (2009) proposed that defects in glycolytic metabolism and increased fatigability in dystrophic muscle may be caused in part by the loss of positive allosteric interactions between nNOS and PFK.
Miura et al. (2009) found that GW501516, a peroxisome proliferator-activated receptor PPAR-beta/delta (PPARD; 600409) agonist, stimulated utrophin A (UTRN; 128240) mRNA levels in mdx muscle cells, through an element in the utrophin A promoter. Expression of PPARD was greater in skeletal muscles of mdx versus wildtype mice. Over a 4-week trial, treatment increased the percentage of muscle fibers expressing slower myosin heavy chain isoforms and stimulated utrophin A mRNA levels, leading to its increased expression at the sarcolemma. Expression of alpha-1-syntrophin (SNTA1; 601017) and beta-dystroglycan (DAG1; 128239) was also restored to the sarcolemma. The mdx sarcolemmal integrity was improved, and treatment also conferred protection against eccentric contraction-induced damage of mdx skeletal muscles.
Long et al. (2014) used clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9)-mediated genome editing to correct the Dmd mutation in the germline of mdx mice, and then monitored muscle structure and function. Genome editing produced genetically mosaic animals containing 2 to 100% correction of the Dmd gene. The degree of muscle phenotypic rescue in mosaic mice exceeded the efficiency of gene correction, likely reflecting an advantage of the corrected cells and their contribution to regenerating muscle. Long et al. (2014) anticipated technologic advances that would facilitate genome editing of postnatal somatic cells, a strategy that may allow correction of disease-causing mutations in the muscle tissue of patients with Duchenne muscular dystrophy.
Moorwood and Barton (2014) found cleaved CASP4 (602664) in muscle biopsies from DMD patients, but not in healthy controls, suggesting ER stress and activation of the unfolded protein response (UPR). Expression of both the pro and cleaved forms of Casp12 (608633), the mouse functional equivalent of human CASP4, was also elevated in muscles in the mdx mouse model of DMD, concomitant with elevated markers of ER stress. Knockout of Casp12 in mdx mice tended to preserve muscle function compared with mdx muscle, with 75% recovery of specific force generation and resistance to eccentric contractions. Compensatory hypertrophy usually found in mdx muscle was normalized in the absence of Casp12, which was due to decreased fiber size rather than a shift in fiber type. Deletion of Casp12 did not reduce mdx muscle fibrosis or appearance. Muscle fiber degeneration in mdx mouse was reduced to almost wildtype levels in Casp12 -/- mdx muscle. Moorwood and Barton (2014) concluded that deletion of Casp12 promoted muscle fiber survival in mdx mice and that aberrant UPR activation may contribute to DMD pathogenesis in humans.
In addition to its presence in muscle, dystrophin is also found in vasculature, and its absence results in vascular deficiency and abnormal blood flow. Since Flt1 is a decoy receptor for vascular endothelial growth factor (VEGF; 192240), both homozygous (Flt1 -/-) and heterozygous (Flt1 +/-) Flt1 gene knockout mice display increased endothelial cell proliferation and vascular density during embryogenesis. To create a mouse model of DMD with increased vasculature, Verma et al. (2010) crossed mdx mice with Flt1 knockout mice. Flt1 +/- and mdx:Flt1 +/- adult mice displayed a developmentally increased vascular density in skeletal muscle compared with wildtype and mdx mice, respectively. The mdx:Flt1 +/- mice showed improved muscle histology compared with mdx mice, with decreased fibrosis, calcification, and membrane permeability. Functionally, the mdx:Flt1 +/- mice had an increase in muscle blood flow and force production compared with mdx mice. Because utrophin (128240) is upregulated in mdx mice and can compensate for the lacking function of dystrophin, Verma et al. (2010) created a triple-mutant mouse (mdx:utrophin -/-:Flt1 +/-). The mdx:utrophin -/-:Flt1 +/- mice also displayed improved muscle histology and significantly higher survival rates compared with mdx:utrophin -/- mice, which showed more severe muscle phenotypes than mdx mice. Verma et al. (2010) suggested that increasing the vasculature in DMD may ameliorate the histologic and functional phenotypes associated with this disease.
Amoasii et al. (2018) used adeno-associated viruses to deliver CRISPR gene-editing components to 4 dogs with the deltaE50-MD dog model of DMD and examined dystrophin protein expression 6 weeks after intramuscular delivery in 2 dogs or 8 weeks after systemic delivery in 2 dogs. After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. Amoasii et al. (2018) concluded that these large-animal data supported the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.
Using antibodies directed against the N terminus of dystrophin, Bulman et al. (1991) identified a truncated protein in a patient with Duchenne muscular dystrophy (DMD; 310200). Antibodies against the C terminus failed to identify any cross-reactive material, a result consistent with premature termination of dystrophin translation. The estimated molecular mass of 126 kD predicted the approximate location of the mutation in the mRNA and in the gene. Sequencing of cloned PCR products from patient muscle cDNA and direct sequencing of amplified patient genomic DNA showed a G-to-T transversion (GAG to TAG) at position 3714 resulting in a change of glutamic acid codon 1157 to an amber stop codon. This was the first reported case of a point mutation in DMD in man.
In 1 of 7 patients with Becker muscular dystrophy (BMD; 300376) in whom analysis of dystrophin by immunoblotting showed a full-sized molecule produced in reduced abundance compared with controls, Bushby et al. (1991) found absence of one of the expected fragments from the promoter region of the DMD gene. They had used PCR with 3 sets of primers within the promoter region, followed by dot blot and restriction analysis. A large deletion was excluded by the finding of normal-sized fragments on amplification with the other primer sets. The patient had no family history of muscle disease, and early motor milestones and mobility were entirely normal. From the age of 5 years, however, he had experienced cramping muscle pains in his calves and thighs, severe enough to limit his exercise potential. The pains were not associated with contractures and cleared in approximately 1 hour on resting as a child, although at the age of 35 they could persist for up to 24 hours. Exceptionally heavy exercise was associated with the passage of dark urine, but myoglobinuria was never proven. From his mid-teens, he also experienced pain in his hands and shoulders on heavy lifting. The severity and persistence of cramps resembled those in the family described by Gospe et al. (1989). No muscle weakness was noticed until the age of about 30 when he began to have difficulty climbing stairs. This weakness was slowly progressive; at age 40 he had mildly lordotic gait and required 2 railings to climb stairs and support on his thighs to rise from a chair or the floor. Serum CPK levels were very high and an electrocardiogram showed incomplete right bundle branch block and Q waves in leads III and aVR. Dystrophin was still produced at 73% of normal abundance, suggesting either that the promoter retains its function at reduced efficiency or that there are additional sequences that can control dystrophin expression in muscle. Boyce et al. (1991) also identified an individual with specific deletion of the dystrophin muscle promoter, giving rise to Becker muscular dystrophy.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Roberts et al. (1992) identified a G-to-T transversion of nucleotide 2999 of the DMD gene, resulting in a change of glutamine-931 to 'stop.'
In a patient with Duchenne muscular dystrophy (DMD; 310200) of intermediate severity, Roberts et al. (1992) identified a C-to-T transition at nucleotide 5759 of the DMD gene that resulted in conversion of glutamine-1851 to a stop codon. The clinical severity was intermediate between that of Duchenne and Becker muscular dystrophies.
In a male with Duchenne muscular dystrophy (DMD; 310200), Roberts et al. (1992) identified a C-to-T transition at nucleotide 9152 resulting in conversion of arginine-2982 to 'stop.'
In a patient with Duchenne muscular dystrophy (DMD; 310200) and mental retardation, Roberts et al. (1992) identified a change from GT to GA in the donor splice site of intron 68 which resulted in skipping of exon 68 (nucleotides 10016-10182). The loss of sequence from the transcripts caused frameshift in this patient, with premature termination of translation.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Roberts et al. (1992) observed a C-to-T transition at nucleotide 10316 which converted the arg codon 3370 to 'stop.'
In a patient with Duchenne muscular dystrophy (DMD; 310200), Roberts et al. (1992) identified a point mutation resulting in deletion of exons 73-76 (nucleotides 10537-11129). Frameshift had resulted after leucine-3444.
In a patient with Duchenne muscular dystrophy (DMD; 310200) of intermediate severity, Roberts et al. (1992) observed a deletion of thymine nucleotide 10662 leading to frameshift and premature termination at leucine-3485. Lenk et al. (1993) identified this mutation in a patient with Duchenne muscular dystrophy.
By chemical mismatch cleavage, Kilimann et al. (1992) identified a single nucleotide insertion, a T, in a contiguous stretch of 4 T residues, which resulted in a frameshift with a stop codon in the new reading frame 13 codons downstream, in a patient with Duchenne muscular dystrophy (DMD; 310200). The deduced translation product would thus end after only 13% of the dystrophin amino acid sequence, which would be expected to be nonfunctional. The mother was a carrier of the mutation.
In a patient with Duchenne muscular dystrophy (DMD; 310200) and no detectable deletion or duplication, Kilimann et al. (1992) used chemical mismatch cleavage to identify replacement of a normal AG dinucleotide by a single T. This resulted in frameshift, the new reading frame being terminated by a stop codon 11 triplets downstream from the mutation, at the beginning of exon 49. The deduced polypeptide broke off after 65% of the length of normal dystrophin, losing the last quarter of its triple-helical rod and its unique cysteine-rich and C-terminal domains. It is therefore probably nonfunctional.
By analysis of ectopic transcription, otherwise known as illegitimate or leaky transcription, in peripheral blood lymphocytes, using reverse transcription and PCR, Rininsland et al. (1992) identified deletion of exon 21 in a patient with Duchenne muscular dystrophy (DMD; 310200).
In an addendum, Rininsland et al. (1992) stated that they had identified a genomic deletion of exon 18 in a patient with Duchenne muscular dystrophy (DMD; 310200) by ectopic transcript analysis.
In 2 brothers with Duchenne muscular dystrophy (DMD; 310200), Clemens et al. (1992) demonstrated an ochre chain termination codon at amino acid position 2319; a C-to-T transition at nucleotide 7163 was responsible for the change. In studies of genomic DNA from the affected boys, no major gene rearrangement had been noted; however, absence of a HindIII Southern fragment containing the proximal portion of exon 48 led to the identification of a point mutation that created a new HindIII restriction site in that exon.
Using the heteroduplex method for screening 5 DMD (310200) exons containing CpG dinucleotides in 110 patients with Duchenne muscular dystrophy (DMD; 310200) without detectable deletions or duplications, Prior et al. (1993) identified 2 different nonsense mutations and a single base deletion, all occurring in exon 19. They stated that this was the first report of a clustering of small mutations in the dystrophin gene. Three patients were identified who had aberrantly migrating exon 19 PCR products. Sequencing of each heteroduplex showed that patient 1 had a nonsense mutation due to a C-to-T transition at nucleotide 2510, changing a CGA (arg) codon to TGA (stop). Patient 2 had deletion of 1 of the 3 cytosines present at nucleotides 2568-2570. The resulting frameshift converted leucine-787 to tryptophan and caused a stop at codon 792, 6 triplets downstream from the mutation at the end of exon 19 (300377.0016). Patient 3 had a G-to-T transversion at nucleotide 2522 converting a GAG (glu) codon to TAG (stop) (300377.0017). No neutral polymorphisms were found in exon 19 or in the other 4 exons screened, namely, 6, 7, 9, and 14.
See 300377.0015 and Prior et al. (1993).
See 300377.0015 and Prior et al. (1993).
In a family with an uncle and nephew with Becker muscular dystrophy (BMD; 300376) and a partial deletion of the DMD gene, Laing et al. (1992) found complete deletion of the gene in the fetus from a terminated pregnancy in a sister of the uncle. Markers indicated that the same X chromosome was affected in the 2 cases. Laing et al. (1992) discussed the alternative possibilities of chance appearance and premutation. In later studies of this family, Wilton et al. (1993) demonstrated that the primary mutation responsible for Becker muscular dystrophy was a splice site alteration. RNA from a muscle biopsy of one of the BMD patients in the family was analyzed using RT-PCR to study the mature gene transcript. Exon 19 was deleted from the dystrophin mRNA but present at the genomic level. The loss of exon 19 was found to be associated with an A-to-C transversion in the third nucleotide of the 5-prime splice site of intron 19. Low levels of normal-sized dystrophin message and dystrophin were present in this patient. As noted earlier, a splice site mutation is the cause of muscular dystrophy in the golden retriever dog (Sharp et al., 1992).
Roberts et al. (1993) described a point mutation in the DMD gene in a man of Japanese ancestry with Becker muscular dystrophy (BMD; 300376) who, when first seen at the age of 31, complained of difficulties in running and in climbing stairs and had frequent falls. On examination, he had hypertrophy of the calves and upper limb weakness and used Gowers maneuver to raise himself from the floor. A maternal uncle had progressive muscular dystrophy and died suddenly of heart failure at age 18. The proband was confined to a wheelchair at age 36 and died of heart failure at age 43. A single base substitution in the splice acceptor site of exon 57 converted the consensus AG to AC and resulted in aberrant splicing of this exon. Approximately half of the transcripts suffered a frameshifting loss of exon 57 (which would result in premature translational termination after repeat domain 22) and approximately half appeared to use a cryptic splice acceptor site 18 bp 3-prime of the normal one (which would be expected to result in a translation product that differed from the wildtype dystrophin only in the interstitial deletion of 6 amino acids).
Using a heteroduplex technique and direct sequencing of amplified products, Prior et al. (1993) screened 105 nondeletion/nonduplication patients with Duchenne muscular dystrophy (DMD; 310200) for point mutations and found in 1 what they believed to be the first dystrophin missense mutation to be detected as the cause of DMD. The mutation was a T-to-G transversion that resulted in substitution of an evolutionarily conserved leucine by arginine at amino acid 54 in the actin-binding domain. The dystrophin protein produced was properly localized and was present at a higher level than is observed in DMD patients. This suggested that an intact actin-binding domain is necessary for protein stability and essential for function.
In a family in which 4 brothers and 2 of their maternal uncles had dilated cardiomyopathy (CMD3B; 302045), Muntoni et al. (1993) described a deletion of the first muscle exon and the muscle-promoter region of the DMD gene. Although no skeletal muscle weakness was present, serum creatine kinase levels were elevated. They put forth the hypothesis that 'the brain promoter is driving relatively high levels of transcription in skeletal muscle but not in the heart.' Bies (1994) and Towbin and Ortiz-Lopez (1994) raised doubts that the muscle-promoter deletion was specific for cardiomyopathy. Muntoni et al. (1995) stated that the deletion did not remove the brain or Purkinje-cell promoters. Dystrophin was detected immunocytochemically in the skeletal muscle from the family of Muntoni et al. (1993), despite the fact that the deletion eliminated the transcriptional start site of the muscle isoform. In order to determine which promoter was driving dystrophin transcription in skeletal muscle of these individuals, Muntoni et al. (1995) first evaluated the expression of exon 1 of muscle, brain, and Purkinje-cell isoforms in normal human skeletal and cardiac muscles and in mouse brain and cerebellum. In normal patients, they found that, with the exception of minimal expression of the brain isoform, only the muscle isoform is significantly transcribed in skeletal muscle, whereas both the exon 1 muscle and brain isoforms are highly expressed in cardiac muscle. In contrast, the skeletal muscle of the patients with X-linked dilated cardiomyopathy showed expression of both the brain and the Purkinje-cell isoforms. The overexpression of these 2 isoforms in skeletal muscle appeared to be of crucial importance in preventing a myopathy in the affected males. The reason for the severe cardiomyopathy remained speculative in the absence of dystrophin data on the heart. Regulatory sequences in the 5-prime region of intron 1 deleted in the patients may be of importance for dystrophin expression in various tissues. It was also possible that the deletion in this family affected specifically 1 of the 2 dystrophin actin-binding domains.
Wilton et al. (1994) used RT-PCR to identify a larger than normal dystrophin mRNA from 2 brothers with Duchenne muscular dystrophy (DMD; 310200). The increased size of the dystrophin mRNA was due to a splice site mutation at the exon 26/intron 26 junction where a T-to-G substitution prevented normal RNA processing. A cryptic splice site, downstream of the mutation, was activated during processing, resulting in the inclusion of 117 bases of intron 26. This insertion introduced an in-frame stop codon into the mature dystrophin mRNA. Using an allele-specific test, Wilton et al. (1994) found that the mother did not carry the mutation and her oldest daughter, designated as a carrier on the basis of conventional testing and haplotype analysis, also did not carry the DMD mutation. Initial haplotyping of the family had appeared to be straightforward with gonadal mosaicism becoming evident only after allele-specific analysis. The application of linked markers to identify the disease locus for conventional genetic counseling would have been erroneous in this family.
Using nonisotopic PCR-SSCP analysis and direct sequencing, Lenk et al. (1994) detected a gln673-to-ter mutation in families with Duchenne muscular dystrophy (DMD; 310200).
Barbieri et al. (1995) independently detected the same mutation. They used heteroduplex analysis to search for small mutations in a sample of 40 Italian patients with DMD or Becker muscular dystrophy (BMD; 300376) in whom large rearrangements were not found. Direct sequencing of the heteroduplex resulted in the identification of a C-to-T transition inserting a termination codon for gln673 in exon 17 in a patient with severe DMD phenotype. Muntoni et al. (1995) reported studies of dystrophin transcription and expression in the heart of 1 member of this family. Whereas the brain and Purkinje cell isoforms of dystrophin were expressed in the muscle of affected males, dystrophin transcription and expression were absent in the heart, with the exception of the distal Dp71 dystrophin isoform, normally present in the heart. The 43- and 50-kD dystrophin-associated proteins were severely reduced in the heart, despite the presence of Dp71, but not in skeletal muscle. The absence of dystrophin and the down-regulation of the dystrophin-associated proteins in the heart accounted for the severe cardiomyopathy in this family. Muntoni et al. (1995) speculated that the severe effect of the mutation on dystrophin expression in the heart may have been secondary to the removal of cardiac-specific regulatory sequences. This family may represent the first example of a mutation specifically affecting the cardiac expression of the gene that is normally present in both skeletal and cardiac muscles.
Using single-strand conformation analysis of products amplified by PCR to screen the terminal domains of the DMD gene (exons 60-79) of 20 unrelated patients with Duchenne muscular dystrophy (DMD; 310200) or Becker muscular dystrophy (BMD; 300376), Tuffery et al. (1995) detected 2 novel point mutations in 2 DMD patients with mental retardation: a 1-bp deletion in exon 70 (which they called 10334delC) and a 5-prime splice donor site alteration in intron 69 (10294,+1,G-T). Both mutations were predicted to result in premature translation termination of dystrophin. Mental retardation is observed in about 30% of patients with DMD (Emery, 1993). This study added 2 more cases to the series of 5 patients out of 7 with a C-terminal point mutation associated with mental retardation described by Lenk et al. (1993), suggesting a possible involvement of the terminal region of the gene in cognitive impairment. Hodgson et al. (1992) found that the same deletion in different individuals occurred with or without mental impairment and that many different deletions are associated with mental retardation.
Milasin et al. (1996) described a splice donor site mutation in the DMD gene in a family with a severe form of X-linked dilated cardiomyopathy (CMD3B; 302045). Analysis of the DMD muscle promoter, first exon, and intron regions revealed the presence of a single point mutation at the first exon-intron boundary, inactivating the universally conserved 5-prime splice site consensus sequence of the first intron. The mutation was a G-to-T transversion of the first base of the GT dinucleotide consensus sequence. This mutation introduced a new restriction site for MseI, which cosegregated with the disease in the kindred. Expression of the major dystrophin mRNA isoforms (from the muscle-, brain-, and Purkinje cell-promoters) was completely abolished in the myocardium, whereas the brain- and Purkinje cell- (but not the muscle-) isoforms were detectable in skeletal muscle. Immunocytochemical studies with anti-dystrophin antibodies showed that the protein was reduced in quantity but normally distributed in the skeletal muscle, while it was undetectable in cardiac muscle. These findings indicated by the authors that expression of the muscle dystrophin isoform is critical for myocardial function and suggested that selective heart involvement in dystrophin-linked dilated cardiomyopathy is related to the absence in the heart of a compensatory expression of dystrophin from alternative promoters. The proband in this kindred was a 24-year-old male who presented with severe heart failure that had developed in the preceding 6 months. He was completely free of any clinical or laboratory sign of skeletal muscle disease, including increased serum creatine kinase level. Additionally, he had been a competitive basketball player for several years. A younger brother was also affected.
In a patient with Duchenne muscular dystrophy, mental retardation, and absence of the ERG b-wave (DMD; 310200), Lenk et al. (1996) identified a G-to-A transition at nucleotide 10227 (10227G-A) in the DMD gene that resulted in a cys3340-to-tyr substitution within the second half of the dystroglycan-binding domain. Weak traces of dystrophin were found on all muscle fibers. Sarcolemmal staining intensity of the 43-kD beta-dystroglycan was also reduced.
Roberts et al. (1994) reported, in a patient with Becker muscular dystrophy (BMD; 300376), a G-to-T transversion at nucleotide position 301, the first nucleotide of the acceptor site of exon 3, resulting in an abnormal splicing with exon 3 skipping.
In a patient with intermediate muscular dystrophy (a phenotype between Duchenne (310200) and Becker (300376) muscular dystrophy), Roberts et al. (1994) identified a deletion of 2 nucleotides (AG) at position 382 of exon 3 of the DMD gene, leading to a frameshift downstream of threonine-58.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Roberts et al. (1994) identified a C-to-T substitution at nucleotide 386 in exon 3 of the DMD gene, causing a nonsense mutation at position 60.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Kneppers et al. (1993) identified the insertion of an A at position 402 in exon 4 of the DMD gene, resulting in a frameshift downstream from glutamic acid-65 and a truncated protein.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Roberts et al. (1994) identified a C-to-T substitution at nucleotide 460 in exon 4 of the DMD gene, resulting in a stop codon at position 85.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Roberts et al. (1994) identified a C-to-T substitution at nucleotide 641 in exon 6 of the DMD gene, leading to a stop codon at position 145.
In a patient with Becker muscular dystrophy (BMD; 300376), Roberts et al. (1994) identified a C-to-A substitution at nucleotide 711 in exon 6 of the DMD gene, resulting in the substitution of an aspartic acid for alanine-168.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Roberts et al. (1994) identified the deletion of a nucleotide (724C) in exon 6, resulting in a frameshift downstream from leucine-172 and a truncated protein.
In a patient with Becker muscular dystrophy (BMD; 300376), Roberts et al. (1994) identified a T-to-A substitution at nucleotide 899 in exon 8 of the DMD gene, resulting in substitution of asparagine for tyrosine-231.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Nigro et al. (1992) and Prior et al. (1994) identified a C-to-T substitution at nucleotide 932 in exon 8 of the DMD gene, encoding a stop codon at position 242.
Roberts et al. (1994) reported in a patient with Duchenne muscular dystrophy (DMD; 310200) a G-to-T transversion at nucleotide 956 in exon 8, resulting in a stop codon at position 250 and a truncated protein.
Roberts et al. (1994) reported, in a patient with Duchenne muscular dystrophy (DMD; 310200), a deletion of 11 nucleotides at position 989 of exon 8, leading to a frameshift downstream of threonine-261 and a truncated protein.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Kilimann et al. (1992) identified the insertion of a T at position 1554 in exon 12, resulting in a frameshift downstream from leucine-449 and a truncated protein.
In a patient with intermediate muscular dystrophy, Prior et al. (1994) identified a G-to-T transversion at nucleotide 1646 in exon 12, resulting in a stop codon at position 480.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Lenk et al. (1993) identified a C-to-T substitution at nucleotide 1697 in exon 13, encoding a stop codon at position 497.
In a patient with Becker muscular dystrophy (BMD; 300376), Hagiwara et al. (1994) identified a G-to-T transversion at the terminal nucleotide (1810) of exon 13 within the 5-prime splice site of intron 13. The mutation resulted in exon 13 skipping. The predicted polypeptide is a truncated dystrophin lacking 40 amino acids downstream from valine-495.
Roberts et al. (1994) reported, in a patient with Duchenne muscular dystrophy (DMD; 310200), a G-to-A transition at nucleotide 2160 in exon 16, resulting in a stop codon at position 651 and a truncated protein.
Roberts et al. (1994) reported, in a patient with Duchenne muscular dystrophy (DMD; 310200), an A-to-T substitution at nucleotide 2516 in exon 19, resulting in a stop codon at position 770 and a truncated protein.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Saad et al. (1994) identified an A-to-G substitution at nucleotide 2525 in exon 19, changing a glutamic acid for lysine-773.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Matsuo et al. (1990, 1991) identified the deletion of 52 bp out of 88 bp in exon 19. Both the 3-prime and 5-prime ends of exon 19 were present. The mutation introduced a termination codon at residue 791 in exon 20, and resulted in the production of a severely truncated protein.
Roberts et al. (1994) reported, in a patient with Duchenne muscular dystrophy (DMD; 310200), an insertion of 1 nucleotide at position 2928 of exon 21, leading to a frameshift downstream of leucine-907 and a truncated protein.
Roberts et al. (1994) reported, in a patient with Duchenne muscular dystrophy (DMD; 310200), a C-to-T substitution at nucleotide 3329 in exon 23, causing a stop codon at position 1041 and a truncated protein.
Roberts et al. (1994) reported, in a patient with Duchenne muscular dystrophy (DMD; 310200), a G-to-A transition at nucleotide 3396 in exon 24, causing a stop codon at position 1063 and a truncated protein.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Roberts et al. (1994) identified a C-to-T substitution at nucleotide 4421 in exon 30, causing a stop codon at position 1405 and a truncated protein.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Roberts et al. (1994) identified a C-to-T substitution at nucleotide 4622 in exon 32, causing a stop codon at position 1472 and a truncated protein.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Saad et al. (1993) identified a C-to-T transition at nucleotide 6107 in exon 41, encoding a stop codon at position 1967.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Kneppers et al. (1993) identified the deletion of 1 nucleotide (6408delC), resulting in a frameshift downstream from threonine-2067 and a truncated protein.
Roberts et al. (1994) reported a T-to-C substitution at nucleotide 6500 in exon 44 of the DMD gene, causing a stop codon at position 2098 and a truncated protein, in a patient with Duchenne muscular dystrophy (DMD; 310200).
In a patient with Duchenne muscular dystrophy (DMD; 310200), Prior et al. (1993) identified a C-to-T substitution at nucleotide 6581 in exon 44, encoding a stop codon at position 2125.
Roberts et al. (1994) identified the deletion of 17 bp, from 6982A to 6998C in exon 47, in the DMD gene, resulting in a frameshift downstream from glutamic acid-2259 and a truncated protein, in a patient with Duchenne muscular dystrophy (DMD; 310200).
Roberts et al. (1994) reported a C-to-T substitution at nucleotide 6998 in exon 47 in the DMD gene, causing a stop codon at position 2264 and a truncated protein, in a patient with Duchenne muscular dystrophy (DMD; 310200).
Roberts et al. (1994) reported the insertion of 1 nucleotide (A) at position 7188 in exon 48 in the DMD gene, resulting in a frameshift downstream from glutamic acid-2331 and a truncated protein, in a patient with Duchenne muscular dystrophy (DMD; 310200).
Roberts et al. (1994) reported a G-to-A transition at nucleotide 7306, the first nucleotide of the donor site of exon 48 in the DMD gene, resulting in an abnormal splicing and the skipping of exon 48 in a patient with Duchenne muscular dystrophy (DMD; 310200).
In a patient with Duchenne muscular dystrophy (DMD; 310200), Winnard et al. (1992) identified a substitution of 2 nucleotides (GG to AT) at position 7609-10 in the DMD gene, encoding a stop codon in position 2468.
This variant, formerly titled DUCHENNE MUSCULAR DYSTROPHY, has been reclassified based on a review of the gnomAD database by Hamosh (2018).
In a patient with Duchenne muscular dystrophy (DMD; 310200), Lenk et al. (1994) identified an A-to-T substitution at nucleotide 8937 in exon 59 in the DMD gene, substituting a valine for glutamic acid-2910.
Hamosh (2018) found that the E2910V variant was present in 4,287 of 199,997 alleles and in 53 homozygotes and 1,379 hemizygotes in the gnomAD database (April 19, 2018).
This variant, formerly titled DUCHENNE MUSCULAR DYSTROPHY, has been reclassified based on a review of the gnomAD database by Hamosh (2018).
In a patient with Duchenne muscular dystrophy (DMD; 310200), Lenk et al. (1994) identified an A-to-G substitution at nucleotide 8942 in exon 59, substituting an aspartic acid for asparagine-2912.
Hamosh (2018) found that the N2912D variant was present in 4,370 of 200,085 alleles and in 59 homozygotes and 1,416 hemizygotes in the gnomAD database (April 19, 2018).
This variant, formerly titled BECKER MUSCULAR DYSTROPHY, has been reclassified based on a review of the gnomAD database by Hamosh (2018).
In a patient with Becker muscular dystrophy (BMD; 300376), Lenk et al. (1994) identified an A-to-G substitution at nucleotide 8970 in exon 59 in the DMA gene, substituting an arginine for histidine-2921.
Hamosh (2018) found that the H292R variant was present in 5,130 of 200,041 alleles and in 42 homozygotes and 1,923 hemizygotes in the gnomAD database (May 8, 2018).
Roberts et al. (1994) reported a C-to-A substitution at nucleotide 9405 in exon 62 of the DMD gene, causing a stop codon at position 3066 and a truncated protein, in a patient with Duchenne muscular dystrophy (DMD; 310200).
Roberts et al. (1994) reported the deletion of 4 bp, from 9679T to 9682T in exon 65 of the DMD gene, in a patient with Duchenne muscular dystrophy (DMD; 310200). The deletion resulted in a frameshift downstream from isoleucine-3157 and a truncated protein.
Lenk et al. (1993) identified, in a patient with Duchenne muscular dystrophy (DMD; 310200), a G-to-A transition at nucleotide 9771, the first nucleotide of the donor site of exon 65, resulting in an abnormal splicing, the skipping of exon 65, and a truncated protein.
Lenk et al. (1993) identified a C-to-T substitution at position 10349 of the DMD gene, encoding a stop codon at position 3381, in a patient with Duchenne muscular dystrophy (DMD; 310200).
In a patient with intermediate muscular dystrophy, Lenk et al. (1993) identified a G-to-A transition at nucleotide 10431 of the DMD gene, the first nucleotide of the donor site of exon 70, resulting in a frameshift downstream from lysine-3374 and a truncated protein.
In a patient with Duchenne muscular dystrophy (DMD; 310200), Lenk et al. (1993) identified a G-to-T transversion at nucleotide 10431 of the DMD gene, the fifth nucleotide of the donor site of exon 70. The mutation resulted in a frameshift downstream from lysine-3374 and a truncated protein.
In a patient with Becker muscular dystrophy (BMD; 300376), Lenk et al. (1993) identified a C-to-T substitution at nucleotide 10470 in exon 71 of the DMD gene, substituting a valine for alanine-3421.
Roberts et al. (1994) reported the deletion of 1 nucleotide (10683C) in exon 74 of the DMD gene, resulting in a frameshift downstream from alanine-3492 and a truncated protein, in a patient with Becker muscular dystrophy (BMD; 300376).
In a patient with Duchenne muscular dystrophy (DMD; 310200), Lenk et al. (1993) identified the substitution of 8 nucleotides by a G at position 10692 in the DMD gene, resulting in a frameshift downstream from leucine-3495 and a truncated protein.
Ortiz-Lopez et al. (1997) used SSCP analysis and direct sequencing to identify the causative mutation in a large North American family with X-linked cardiomyopathy (CMD3B; 302045). An A-to-G mutation at nucleotide 1043 was present only in affected males and carriers. The mutation changed a highly conserved threonine to alanine at amino acid position 279 within the H1 region of the dystrophin molecule. This change is predicted to result in loss of cardiac myocyte membrane integrity and eventual loss of contractile function.
Shiga et al. (1997) found a nonsense mutation, glu1211-to-ter (E1211X), due to a G-to-T transversion at the twenty-eighth nucleotide of exon 27 (3839G-T) in the DMD gene of a Japanese patient with Becker muscular dystrophy (BMD; 300376). Partial skipping of exon 27 resulted in the production of truncated dystrophin mRNA, although the consensus sequences for splicing at both ends of exon 27 were unaltered. To determine how E1211X induced exon 27 skipping, Shiga et al. (1997) examined the splicing enhancer activity of the purine-rich region within exon 27 in an in vitro splicing system using chimeric Drosophila doublesex (dsx) gene pre-mRNA in HeLa cell nuclear extract. The mutant sequence containing 3839G-T abolished splicing enhancer activity of the wildtype purine-rich sequence for the upstream intron in this chimeric pre-mRNA. An artificial polypurine oligonucleotide mimicking the purine-rich sequence of exon 27 also showed enhancer activity that was suppressed by the introduction of a T nucleotide. Furthermore, the splicing enhancer activity was more markedly inhibited when a nonsense codon was created by the inserted T residue. This was the first evidence that partial skipping of an exon harboring a nonsense mutation is due to disruption of a splicing enhancer sequence.
In a family with X-linked dilated cardiomyopathy (CMD3B; 302045), Ferlini et al. (1998) found that affected members had an Alu-like mobile element rearranged into the DMD gene 2.4 kb downstream from the 5-prime end of intron 11. The rearrangement activated 1 cryptic splice site in intron 11 and produced an alternative transcript containing the Alu-like sequence and part of the adjacent intron 11, spliced between exons 11 and 12. Translation of the alternative transcript was truncated because of the numerous stop codons present in every frame of the Alu-like sequence. Only the mutant mRNA was detected in the heart muscle, but in the skeletal muscle it coexisted with the normal one. Ferlini et al. (1998) suggested that this Alu-like sequence could represent a novel class of repetitive elements, reiterated and clustered with some known mobile elements and capable of transposition.
In a 9.5-year-old male with Duchenne muscular dystrophy (DMD; 310200) in whom intelligence could not be tested and who had no reading ability, Moizard et al. (2000) identified a premature translation termination of the Dp71 transcript: a 9776C-T transition in exon 66, causing an arg3190-to-stop substitution.
Ginjaar et al. (2000) studied an X-linked muscular dystrophy family in which different phenotypes occurred in 3 males: a severely affected patient with Becker muscular dystrophy (BMD; 300376) with cardiomyopathy, a mildly affected patient with BMD, and an apparently healthy male with elevated serum creatine kinase levels. In the muscle biopsy specimen of the mildly affected patient, 1 of 4 antibodies (NCL-DYS1) showed absence of dystrophin. The protein truncation test detected a truncated dystrophin for both muscle tissue and lymphocytes of this patient with an additional nearly normal-sized fragment in muscle. Genomic sequence analysis revealed a 4148C-T mutation in exon 29 of the DMD gene, resulting in an arg1314-to-ter mutation. Sequence analysis of the mRNA fragment of the larger peptide showed skipping of exon 29, restoring an open reading frame. Consequently, the epitope of the antibody NCL-DYS1 maps to exon 29. The variable clinical features of the 3 males from healthy to severely affected seems, therefore, to be related to the level of skipping of exon 29. This finding underscored the future potential of gene therapeutic strategies aimed at inducing exon skipping in DMD to generate a much milder disease.
In a male with Duchenne muscular dystrophy (DMD; 310200), van Essen et al. (2003) identified a 1-bp deletion, 377delA, in the DMD gene. The deletion caused a frameshift and resulted in a stop codon 45 bp downstream, in codon 141. The mother was mosaic for the mutation; she passed 'risk haplotype' to her other son, who was healthy.
In a patient with severe Duchenne muscular dystrophy (DMD; 310200), Todorova et al. (2003) identified a 16-bp deletion in exon 44 of the DMD gene, which led to a frameshift and premature translation termination. The patient had become wheelchair bound at the age of 10 years. Myocardial damage was detected at the age of 14 years and he died from cardiomyopathy at the age of 18.
In 2 unrelated patients with Becker muscular dystrophy (BMD; 300376), Tuffery-Giraud et al. (2003) identified 2 deep intronic mutations in the DMD gene, causing the aberrant inclusion of a pseudoexon in the mature transcripts. These 2 mutations were identified by use of RT-PCR on transcripts isolated from muscle. The first abnormally large transcript resulting from a 58-bp insertion between exon 62 and exon 63 was identified in a BMD patient with mental retardation. The origin of this transcript was a mutation in intron 62 (IVS62-285A-G), which resulted in the occurrence of a high quality donor splice site. The second mutation, IVS25+2036A-G (300377.0081), in intron 25 was identified in a subclinical BMD patient with high creatine kinase levels. The mutation reinforced the strength of a preexisting acceptor splice site, resulting in activation of an intronic pseudoexon of 95 bp. By using denaturing high performance liquid chromatography (DHPLC), the patient's mother was found to be a somatic mosaic. The insertion of these newly recognized extra exons led to premature termination codons, but some degree of normal splicing was taking place in both patients.
See 300377.0080 and Tuffery-Giraud et al. (2003).
In 6 of 141 patients with Duchenne muscular dystrophy (DMD; 310200) previously found to be negative for large deletions in the DMD gene, Buzin et al. (2005) identified an 8713C-T transition in a CpG dinucleotide in exon 59 of the DMD gene, resulting in an arg2905-to-ter (R2905X) substitution. Haplotype analysis indicated that all 6 mutations occurred independently.
In a 12-year-old boy with asymptomatic dystrophinopathy (see 300376), Yagi et al. (2003) observed a 132-bp insertion between exons 2 and 3 of the DMD gene in both lymphocyte and muscle mRNA. Sequencing the regions flanking the insertion revealed a +5591T-A transversion in IVS2, creating an AG dinucleotide consensus sequence for a splicing acceptor site predicted to produce a novel exon structure that is then incorporated into dystrophin mRNA. The 44-codon sequence is inserted between 2 actin-binding sites which would presumably disturb the localization of dystrophin; immunohistochemical staining of a muscle biopsy from this patient revealed that the N-terminal domain was not stained and the rod- and C-terminal domains were stained in a patchy and discontinuous manner. Yagi et al. (2003) stated that the creation of a splice acceptor site by a single nucleotide change leading to an extra exon structure is a novel molecular mechanism in human disease.
In a Japanese boy with a severe form of Duchenne muscular dystrophy (DMD; 310200), Tran et al. (2007) identified a 5985T-G transversion in exon 42 of the DMD gene, resulting in a tyr1995-to-ter (Y1995X) substitution and a nonfunctional protein. RNA analysis of the patient's skeletal muscle showed exclusive expression of the truncated transcript; however, RNA analysis of the patient's leukocytes showed that the 5985T-G transversion also created a novel splice acceptor site, resulting in aberrant splicing and production of 2 partially functional dystrophin proteins. The findings suggested tissue-specific splicing regulation, which was likely due to trans-elements rather than cis-elements. Tran et al. (2007) suggested that modulation of DMD splicing in cases such as this could be a potential therapeutic target.
Kerst et al. (2000) found that haploinsufficiency for a 387G-T transversion in the MYF6 gene, resulting in an ala112-to-ser mutation (159991.0001), caused a mild form of centronuclear myopathy (160150). The same mutation in the proband's father, who also had deletion of exons 45 to 47 in his DMD gene, resulted in a conversion from the expected mild course to a severe course of Becker muscular dystrophy (BMD; 300376). The father was wheelchair-bound at the age of 21 years. Kerst et al. (2000) noted that the deletion of exons 45 to 47 in the DMD gene is known to be associated with a mild to moderate course of BMD.
In a 58-year-old man from Utah with a mild form of Becker muscular dystrophy (BMD; 300376), Flanigan et al. (2003) identified a 9G-A transition in exon 1 of the DMD gene, resulting in a trp3-to-ter (W3X) substitution. The patient had onset of muscle weakness at age 20 years and had not lost ambulation by age 58. Gurvich et al. (2009) reported follow-up of the patient reported by Flanigan et al. (2003), who subsequently lost ambulation at age 62 years. His brother, who also had the mutation, had only minimal difficulty climbing stairs at age 62. Gurvich et al. (2009) identified the W3X mutation in affected individuals of 5 additional families with mild BMD manifested as increased serum creatine kinase and sometimes exertional myalgia in the first 2 decades. SNP analysis indicated a founder effect in the Utah population, suggesting that maintenance of the allele was most likely due to the exceptionally mild phenotype.
Using immunofluorescent studies, Gurvich et al. (2009) found that patients with the W3X mutation expressed dystrophin protein in muscle fibers, although the level was decreased compared to controls and the W3X-mutant protein lacked exon 1 and the N-terminal sequence. Studies with reporter constructs, which encompassed exons 1 to 9 of the muscle isoform of DMD, identified 2 alternative translation start sites in exon 6 of the DMD gene, resulting in the synthesis of a 60-kD protein instead of the wildtype 72-kD protein. The findings suggested that this resultant shortened protein retains enough residual activity to significantly ameliorate the severe phenotype that would be expected to result from a truncating mutation in exon 1 of the DMD gene.
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