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Myotonic Dystrophy: Discussion of Molecular Basis

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Myotonic dystrophy 1 (DM1) is a dominant, neuromuscular disease which represents the most common form one of muscular dystrophy with a frequency of 1 in 8,000. Today, there is no cure for this disease. Clinical manifestations vary from the almost asymptomatic condition to the deadly form of disease associated with increased disease severity in generations with reduction of age of onset.

Identification of the gene responsible for the disease and discovery of a CTG trinucleotide expansion as the mutation for DM1 explained many aspects of the clinical features of DM1. However, the development of treatment requires elucidation of the molecular mechanisms of DM1 pathogenesis, explaining how the increase of the length of CTG repeats induces disease. The solution of this problem is complicated because the CTG expansion is located in the 3'-untranslated region rather than in the coding region of the mutant gene. Because of this unusual feature of the DM1 mutation, it took almost a decade to reveal the most significant features of the molecular pathogenesis of DM1. This review focuses on the latest data related to the molecular basis of instability of CTG repeats and the complex molecular pathogeneses mediated by unstable CTG/CUG repeats in DM1 patients.

DM1 Mutation Is an Expansion of CTG Trinucleotide Repeats

DM1 is an autosomal, dominant, neuromuscular disease characterized by involvement of multiple systems.1There are two forms of disease, adult and congenital. The adult form is characterized by myotonia, muscle weakness and wasting, cataracts, cardiac abnormalities, testicular atrophy, and insulin resistance. The most severe form of DM1, congenital DM1, is associated with hypotonia, mental retardation, and delayed muscle maturation.

The CTG Expansion Is an Unstable Mutation within the 3' UTR of the DMPK Gene

The CTG triplet repeat expansion in the normal populations consists of 5–37 units; however, in patients with DM1 the length of CTG expansion is significantly increased up to many thousands of repeats. The number of CTG repeats within the DMPK gene positively correlates with the severity of the symptoms and negatively correlates with age, a phenomenon known as “anticipation”.

Once into the expanded disease-associated range, the DM1 CTG repeat becomes highly unstable. The germline mutation rate is essentially 100% and highly biased toward further increases in repeat length. Since the length of the repeat is positively correlated with disease severity and inversely correlated with the age of onset of symptoms, these increases account for the high levels of clinical anticipation observed in DM1 families.2 The length changes observed are usually large such that the repeat rapidly expands from the range associated with the late onset form of the disease (60 to 100 repeats), through the adult onset form of the disease (200 to 500 repeats), to the congenital form of the disease (700 to 4,000 repeats), often in as few as three generations. Small expansions in humans (50 to 80 repeats) are particularly biased toward large expansions in the male germline, accounting for the excess of transmitting grandfathers in DM1 pedigrees.3 In contrast, larger expansions in the range 200 to 500 repeats, are most likely to expand further when transmitted by a female, explaining the almost complete association between maternal transmission and congenital DM1.4 Instability in the soma is also extensive and follows reproducible dynamics. Multiple small mutations biased toward expansions occur throughout life resulting in a gradual increase in the level of variation and the average repeat length within a tissue.5–7 The pattern of variation between different somatic tissues appears to be conserved, but the rate at which variation accumulates is tissue specific. Most interestingly, the repeat length observed in muscle is always much larger than that observed in blood DNA.5,8–10 This is intriguing considering the tissue specificity of DM1 symptoms and the post-mitotic nature of muscle in the adult. It seems reasonable to assume therefore that age-dependent, tissue-specific, expansion-biased somatic mosaicism contributes toward the progressive nature and tissue specificity of the symptoms. Although analysis of DM1 patient samples has yielded a number of significant insights into the dynamics of the expanded repeats, the utility of such an approach is limited by the availability of appropriate samples and the confounding effects of allele length, age and genetic background.

Mouse Models of Unstable DNA

In order to provide a system in which the factors effecting repeat stability may be more precisely defined, a number of mouse models containing expanded CTG.CAG repeat arrays have been generated. These include models for a number of loci and with varying amounts of flanking DNA in simple transgenics,11–19 and more recently recombination into the murine homologue.20–22 To date, two models using transgenes derived from the human DM1 locus have been reported14,16(Fig. 1a) The Dmt162 transgene contains 162 CTG.CAG repeats, but only incorporates ∼700 bp of the DM1 flanking region and none of the coding DNA.14 Five transgenic mouse lines with random genomic insertion sites were generated with this construct, all of which were unstable in the germline. Although the rates of germline mutation were high, up to 70%, the length change events observed were relatively small, usually less than +/−10 repeats. Sex-specific differences were observed with expansions predominating in transmissions from males and contractions predominating in female transmissions. In addition, there were dramatic position effects with mutation rates varying from 10% to 70% dependent on the integration site. In order to determine if sequences flanking the human DM1 repeat might be necessary to replicate the human dynamics of the repeat, mice have also been generated using much larger cosmid constructs.16 The cosmid construct used spanned 45 kb of the DM1 region and includes the upstream gene DMWD in addition to DMPK and SIX5. Multiple lines have been generated with 20 (DM20), 55 (DM55) and 300 (DM300) CTG.CAG repeats.16,23 Not surprisingly, the repeat in the DM20 lines was very stable with no mutations observed during germline transmission. The repeat was moderately unstable (germline mutation rates 0 to 3%) in the DM55 lines and biased toward small expansions (mostly +1 repeats). The repeat was dramatically more unstable in the germline of the DM300 mice with mutation rates approaching 100%. These were again mostly biased toward expansions (∼90%). The length changes observed were much larger than have been observed in other murine models; mean ength change +9 repeats in males and +20 repeats from females. However, these length changes are still an order of magnitude smaller than would be expected for similar sized alleles at the human DM1 locus.3,5 Nonetheless, the length changes observed in both the Dmt162 and DM55 and DM300 lines are comparable to the dynamics observed at many of the more stable human loci such as the spinocerebellar ataxia type 3, spinal and bulbar muscular atrophy and dentatorubral pallidoluysian atrophy loci.24 Thus, it currently remains unclear whether the large germline expansions observed at the human DM1 locus are reproducible in mice. Failure so far might be due to the omission of critical cis-acting sequences in transgene constructs, the inability of critical cis-acting human sequences to mouse genome. Alternatively, the effect may simply reflect the short life cycle of the mouse. Transmitted expansion sizes have been shown to be age dependent in a number of the mouse models,15,18,23,25 and if the length changes observed after one to two years in mice were extrapolated to the 20 to 40 year reproductive age of humans then they would indeed be comparable to even the most unstable human loci such as DM1.

Figure 1a. The human DM1 genomic region and mouse transgenes.

Figure 1a

The human DM1 genomic region and mouse transgenes. Shown are the human DM1 region including the upstream DMWD gene, DMPK and the downstream SIX5 gene, the position of the CTG repeat and the repeat containing CpG island. Also shown are the five transgene (more...)

These lines have also been used to determine if somatic instability can be replicated in the mouse. In contrast to the failure to fully replicate germline instability, somatic instability appeared to be highly reproducible in the mouse. Somatic mosaicism in Dmt162, DM55 and DM300 mice was expansion-biased, tissue-specific and age-dependent.23,26,27 Moreover, the length changes observed were large with some cells in Dmt162 and DM300 mice containing additional expansion of more than 200 repeats. Most interestingly, the degree and precise tissue specificity of repeat instability was highly line-specific. Only one of the five Dmt162 lines displayed significant levels of somatic instability, the remainder remaining very stable throughout life. All of the DM300 lines showed somatic instability, but the absolute tissue specificity differed between them despite the large amount of human genomic DNA that is incorporated. Overall these data suggest that local sequence context may influence the general degree of instability, but that larger scale effects may moderate the tissue specificity. Consistent with these predominantly position-mediated effects, no association with tissue-specificity and cell turnover have been observed casting doubt on the predominant replication slippage based mechanism of DNA instability. Moreover, no association with transcriptional levels and the tissue-specificity have been observed either.26 However, lines in which the transgenes are not expressed at all appear to the most stable.15These data suggest that the genomic environment consistent with gene expression is necessary, but not sufficient, to facilitate somatic instability.

Mouse models generated to understand some of the other human expansion disease loci15,17,18,20–22similarly recreate the somatic mosaicism observed in the Dmt162, DM55 and DM300 mice. However, the absolute levels of variation reported are not generally as high. This may reflect transgene content, integration site or allele length effects. More likely however, is a failure to use the sensitive single molecule PCR approaches5to detect variation that have been used so successfully in the Dmt162 and DM55 mice.14,26 Very recently, these methods have been used to reveal gross expansions in the striatum of Huntington disease (HD) knock-in mice.28These data suggest that somatic mosaicism may, as with DM1, contribute to the tissue specificity and progressive nature of some the other repeat expansion disorders.

Mice models such as these should prove excellent for further defining the critical factors involved in regulating repeat dynamics. Indeed, transgenics incorporating exon 1 of the human HD gene with an expanded CAG.CTG repeat have been used to reveal that the mismatch repair gene Msh2 is actually required for the development of high levels of somatic mosaicism.29These data shed further doubt on the predominant replication slippage model which would predict that loss of mismatch repair activity would actually increase instability. No doubt further studies such as these using the array of mouse DNA repair variants that are now becoming available will shed further light on the role of these genes in the expansion process.

Molecular Pathogenesis of DM1

The DMPK Protein Is a Novel Kinase

The CTG expansion in DM1 patients is located within the 3' UTR of a novel protein kinase, named DMPK. After the DM1 gene was cloned, major efforts were focused on the expression analysis of DMPK protein in normal tissues and in DM1 patients and on the identification of the biological function of DMPK.

DMPK protein is expressed in many tissues with highest expression in skeletal muscle and heart and localized to the neuromuscular junction.30,31 The protein consists of several domains, including an N-terminal leucine-rich region, a catalytic kinase domain, a C-terminal coiled-coil domain and a membrane association domain. Analyses of biological function of DMPK domains showed that the kinase domain is required for phosphorylation of serines and threonines in substrate molecules,32,33 the coiled-coil domain is necessary for DMPK oligomerization34 and the membrane association domain is involved in peripheral membrane association of the kinase.35

Little is known about the role of DMPK in signal transduction pathways. Several molecules have been proposed as candidates for physiological regulatory factors of DMPK. Since DMPK-related proteins are regulated by Rho family GTPases, small G proteins are considered potential DMPK activators.34 It has been shown that DMPK interacts with Rac-1,36 a protein that belongs to the Rho family. Because members of the Rho family are associated with the actin cytoskeleton and regulate its dynamic interaction with the plasma membrane, DMPK might participate in the regulation of adhesion-dependent pathways.36

One of the most important investigations of DMPK function is identification of its biological substrates. Since myotonia is associated with defects in ion channels, it was suggested that DMPK might be involved in the phosphorylation of ion channels that would affect their function. It was shown that DMPK phosphorylates the b-subunit of voltage-dependent Ca2+-release channel in vitro.33 In agreement with these data, Ca2+ homeostasis was found to be affected in mutant mice deficient for DMPK.37 Analysis of these mice also showed alterations of activity for Na channels.38 Recently, it was shown that DMPK phosphorylates phospholemman, a membrane protein that induces Cl currents.39

Initial hypotheses suggested that DMPK expression might be affected by the CTG expansion in the 3' UTR of the DMPK gene. Immunoanalysis of DMPK protein showed that in a majority of patients, DMPK levels were reduced. However, there are several cases where DMPK protein levels are unchanged or even elevated.40 In order to understand whether alterations of DMPK expression are crucial for the disease phenotype, mouse models where the DMPK gene has been deleted or overexpressed were generated.

Mouse Models of DMPK Function

DMPK is expressed in many tissues in both man and mouse, but is particularly highly expressed in skeletal muscle and heart.30,31 This observation in addition to the location of the CTG.CAG repeat expansion within the transcriptional unit of the gene, made DMPK a prime candidate for mediating the pathogenicity of the DM1 expansion. A mouse model overexpressing human DMPK (Fig. 1b) does show a mild hypertrophic cardiomyopathy and an unexplained increase in neonatal mortality, but no obvious correlation with any of the symptoms observed in DM1 patients.41 However, two independent knockouts of mouse Dmpk(Fig. 1b) have not produced a dramatic phenotype either.41,42 Even mice completely deficient for Dmpk are fully viable and appear morphologically normal. Detailed investigations have revealed some subtle effects. Very old mice do develop a mild skeletal muscle myopathy, but the histological changes and myotonia characteristic of DM1 patients were not reproduced. A convincing cardiac conduction defect has been reported which is similar in nature to that observed in DM1 patients.42–44 Moreover this effect is observed in mice both homo- and heterozygous for the null allele. Dmpk knockout mice developed prolonged AV conduction times and moreover, this defect was age-dependent. There were no cardiac AV problems in 2-month-old mice, but they were observed in older mice (>5 months). Homozygous Dmpk knockout mice showed second- and third-degree AV blocks that were absent in heterozygous or wild-type mice. There were no differences in conduction defects in Dmpk homozygous mice in different age groups. Since the same mice have not shown atrophy, fatty replacements and fibrosis, it seems likely that the conduction defects in patients with DM1 might be associated with the lack of Dmpk, but degeneration of the conduction system might be due to other causes. It is also very interesting that overexpression of DMPK in mice resulted in the development of hypertrophic cardiomyopathy. These data suggest that DMPK directly or indirectly is involved in the development of cardiac defects.

Figure 1b. The mouse myotonic dystrophy type 1 genomic region and replacement alleles.

Figure 1b

The mouse myotonic dystrophy type 1 genomic region and replacement alleles. Shown are the mouse DM1 region including the upstream Dmwd gene, Dmpk and the downstream Six5 gene, the position of the cryptic CTG repeat and the nearby CpG island. Also shown (more...)

There are several possible hypothetical explanations how the lack or induction of DMPK would affect heart function. One possibility is that DMPK might regulate specific ion channels that might be affected in DM1 hearts due to abnormal levels of DMPK kinase. In agreement with this suggestion, Ca2+ homeostasis has been reported to be defective in Dmpk −/− skeletal muscle cells, although the pathophysiological consequences of this effect are unclear.37 Alterations in skeletal muscle sodium channel function have also been reported in Dmpk +/− mice.38

Defects in other organ systems commonly affected in DM1 patients such as the eye, smooth muscle and reproductive tract have not been reported in Dmpk-deficient mice. Thus, although Dmpk appears to be essential for correct functioning of skeletal and cardiac muscle cells, its absence does not appear to contribute significantly to many of the major features associated with DM1 in humans.

Deficiency of Six5 in DM1

There are several genes in the region surrounding the CTG repeat at the DM1 locus45(Fig. 1b), which led to the hypothesis that the expanded repeat might alter the expression of genes in addition to DMPK. Repetitive elements in other areas of the genome, for example at the heterochromatin of telomeres and centromeres, were known to suppress the expression of adjacent genes. For example, studies in Drosophila and other organisms demonstrated that genes positioned adjacent to regions of heterochromatin had an increased probability of being suppressed, sometimes resulting in a variegated expression pattern, termed position effect variegation (PEV). Therefore, it seemed plausible that the repetitive sequence introduced at the DM1 locus with CTG repeat expansion might alter the expression of adjacent genes. This hypothesis was indirectly supported by in vitro studies that demonstrated a high affinity of nucleosomes for the CTG sequence, 46 and subsequently by the in vivo demonstration that the region surrounding the expanded repeat had a more condensed chromatin structure than the wild-type allele.47

The promoter for the SIX5 gene, formerly termed Dystrophia Myotonia Associated Protein (DMAHP), is very close to the repeat and within the region that exhibits expansion induced changes in chromatin structure. The expansion of the CTG repeat does suppress expression of SIX5, since studies in cells from individuals with DM1 demonstrated decreased steady-state levels of the SIX5 transcript.48,49 SIX5 belongs to a family of homeobox transcription factors related to the Drosophila sine oculis gene.50,51 In Drosophila, sine oculis is part of a group of genes critical for eye development. The same network of genes has been conserved in vertebrates, but as multigene families. The family of vertebrate homologues to the Drosophila sine oculis are referred to as the SIX genes, and SIX5 is the family member at the DM1 locus. Different SIX gene family members are expressed in many different cell types during vertebrate development, including the vertebrate eye and lens, as well as in skeletal muscle.

Although much remains to be learned regarding the role of the SIX family of genes in vertebrate development, the little that is known suggests that they might have a role in the pathogenesis of DM1. Studies of gene promoter elements indicated that the SIX family members are important transcription factors for a subset of genes expressed in skeletal muscle and for the expression of subunits of the sodium-potassium ATPase.50,52 Abnormalities of sodium homeostasis have been reported in DM1 and could contribute to the myotonia, the cataracts, the cardiac conduction defects, and central nervous system effects. Therefore, the possible roles in skeletal muscle gene expression and in sodium homeostasis make the SIX5 gene a good candidate regulating some of the critical features of DM1.

As an initial test of the role of the SIX5 gene in human biology, homologous recombination was used to disrupt the murine Six5 gene (Fig. 1b). Mice with a deficiency of Six5 developed cataracts at a young age, strongly suggesting that human SIX5 deficiency might be the cause of the cataracts associated with DM1.53,54It remains possible that other features of DM1 might also be attributed to decreased SIX5 expression, perhaps acting together with a deficiency of DMPK or with a possible gain-of-function role of the CUG repeat in the RNA.

Alterations of RNA Metabolism in DM1

Given the lack of an overt DM1 phenotype in Dmpk knock out mice, several new hypotheses have been suggested. Among those, an RNA-based model has been proven by a number of recent publications. It was initially shown that the levels of DMPK mRNA in patients with DM1 were unchanged within total RNA; however, mRNA levels were significantly reduced within poly(A)+ mRNA.55,56 Moreover, it has been shown that the levels of poly(A)-containing DMPK mRNA was reduced not only from the mutant allele, but also from a normal allele, suggesting that the CTG expansion has a negative effect on the DMPK gene in trans. These data provided a background for a hypothetical RNA model for DM1 disease where trinucleotide repeats might affect genes via association with RNA-binding proteins.55 This suggestion was further supported by the demonstration that DMPK mutant transcripts formed foci within nuclei of DM1 patients.57 Similar foci were identified in cultured cells transfected with CUG-expressing constructs.58 Although the nature of these foci is currently unknown, their ability to hybridize with CAG triplet repeat probes suggests that they are formed by mutant DMPK transcripts.59

The RNA-based hypothesis for DM1 pathogenesis has been recently proven by generation of mouse models expressing large expanded CUG repeats. The simple Te162 transgene that does not express the DMPK coding region but expresses a large CUG repeat tract within the DMPK 3'UTR has been used to reproduce the testicular atrophy associated with DM1 males60(Fig. 1a). More recently, a CUG repeat array has been incorporated into the 3'UTR of a human skeletal muscle a-actin transgene61(Fig. 1a). Expression of a 5 CUG repeat allele had no effect in mice, whereas the expression of a large 250 CUG repeat array resulted in muscular atrophy and myotonia: typical characteristics of DM1 patients. These results provide strong evidence for a major role of RNA CUG repeats in the molecular pathogenesis of DM1 and provide an excellent basis for further determining how the effect of RNA CUG repeats is mediated.

The RNA-based model suggests that the expansion of CUG RNA repeats in DM1 alters (sequesters) specific RNA binding proteins that interact with CUG repeats (Fig. 2). Currently, several RNA-binding proteins are considered as candidate factors sequestered by CUG expansion within DMPK mRNA. This group of proteins includes two distinct protein families: CUGBP1-like proteins and EXP (expansion binding) proteins.

Figure 2. RNA model for DM1 disease.

Figure 2

RNA model for DM1 disease. In DM1 patients, CUG repeat is expanded within the DMPK mRNA. CUGBP1 (shown as open oval) is sequestered by expanded CUG repeats. As a result of this sequestration, DM1 cells are lacking of free protein that affects RNA processing. (more...)

CUGBP1 (CUG RNA-Binding Protein) Is Affected in Patients with DM1

An initial search for CUG RNA-binding proteins identified two RNA-binding proteins that specifically interact with CUG8 repeats.62 One of these proteins, named ss-CRRP, interacts with single-stranded DNA containing CTG repeats as well as with RNA CUG triplet repeats; while another protein, CUGBP1, interacts only with RNA CUG repeats. Comparison of the CUG-binding activity for CUGBP1 and ss-CRRP in normal individuals and in individuals affected with DM1 showed that binding activity for ss-CRRP is unaltered in DM1; however, the binding activity of CUGBP1 is significantly altered.63 Because of this finding, CUGBP1 has been further investigated in detail.

Investigations of CUGBP1 in DM1 patients showed that there are significant disease-associated alterations in protein levels, activity and intracellular distribution of CUGBP1. The level of hypophosphorylated CUGBP1 is increased within nuclei of DM1 patients.64 It has been recently shown that alterations of CUGBP1 expression in DM1 are, at least in part, due to sequestration of CUGBP1 by CUG repeats within the mutant DMPK transcripts65(Fig. 2). Sequestration analysis shows that in addition to CUGBP1, an unknown RNA-binding protein of high molecular weight is involved in heavy RNA-protein complexes formed by expanded CUG repeats, suggesting that mutant DMPK mRNA affects more than one RNA-binding protein. Examination of RNA processing in DM1 tissues demonstrated that two levels of RNA processing are affected by alterations in CUGBP1 expression. Analysis of cardiac troponin T (cTnT) alternative splicing in DM1 heart tissue and skeletal muscle cultures demonstrated that alterations in CUGBP1 led to aberrantly high levels of exon inclusion.66 Splicing of cTnT minigenes in DM1 skeletal muscle cultures indicated the same aberrant pattern as in DM1 patients compared to splicing in skeletal muscle cultures from unaffected controls. Importantly, that aberrant splicing requires a CUGBP1 binding site within the intronic muscle-specific enhancer (MSE), demonstrating that the aberrant splicing is likely to be mediated by CUGBP1 and/or other members of this family (Fig. 3).

Figure 3. CUGBP1 and ETR-3 like factors (CELF proteins) bind cTnT intronic elements (MSEs) that promote exon inclusion in embryonic muscle.

Figure 3

CUGBP1 and ETR-3 like factors (CELF proteins) bind cTnT intronic elements (MSEs) that promote exon inclusion in embryonic muscle.

Investigations of the effect of RNA CUG repeats on CUGBP1 in cultured cells confirmed that CUG repeats alter CUGBP1 expression and suggested a putative mechanism of this effect. Analysis of RNA-CUGBP1 complexes showed that the majority of CUGBP1 is bound to the endogenous RNA containing CUG repeats in DM1 heart tissue.65 Similar sequestration of CUGBP1 has been observed in DM1 cell culture models when cells were transfected with plasmid expressing long CUG repeats.65 Analysis of RNA-CUGBP1 complexes in DM1 cells demonstrated that these complexes contain transcripts with CUG repeats,65 suggesting that CUGBP1 is sequestered by DMPK mRNA. In vivo data suggest that CUGBP1 binds to long CUG expansions and that this binding leads to the stabilization of CUGBP1.65In addition, detailed study of cultured cells expressing RNAs with long expansions (480–1440 CUG repeats) shows that CUGBP1 activity is affected by long CUG repeat sequences, with CUGBP1 activity increasing proportionally to the number of repeats.66 These data suggest that, similar to tissue culture, CUGBP1 is also sequestered by CUG expansion in DM1 patients. It is interesting to note that electron microscopy studies indicated that, under specific in vitro conditions, CUGBP1 preferentially binds to the single-stranded base of double-stranded hairpin structures that are formed by CUG repeats.67 This observation offers the possibility that CUGBP1 can be involved in stabilization/destabilization of secondary structures of RNA containing CUG RNA repeats.

CUGBP1 Belongs to a Conserved Family of Elav RNA-Binding Proteins

Comparison of the nucleotide sequence of CUGBP1 with known RNA binding proteins showed a high level of homology to elav (embryonic lethal abnormal visual phenotype) family proteins.68 Elav proteins are involved in the regulation of a specific sub-class of mRNAs coding for proteins regulating the cell cycle. For example, the binding of elav proteins to c-myc or c-fos mRNAs affects mRNA stability or translation and this leads to alteration of protein levels affecting overall proliferative cellular status. Elav proteins in Drosophila are located in nuclei where they regulate splicing. In contrast, in human cells elav proteins are located in both cytoplasm and nuclei and are involved in multiple steps of RNA processing such as stability and translation. Similar to the elav proteins, CUGBP1 contains three RNA binding domains (RBDs), the distribution of which within CUGBP1 is similar to that observed in elav-like proteins the first two RBDs are located close to each other, but RBDIII is separated from the first two RBDs by a long linker.68 It has been suggested that separation of RBD1+2 and RBD3 might be associated with two distinct biological functions of RNA-binding proteins and with different sequence specificity.

CUGBP1 Targets

Since CUGBP1 is affected in DM1 patients, identification of its native mRNA targets is important for understanding CUGBP1 downstream pathways. So far, two RNAs regulated by CUGBP1 have been characterized in detail. They include pre-mRNA coding for cardiac Troponin T (cTnT)67 and the mRNA for a transcription factor CCAAT/Enhancer Binding Protein b, C/EBPb.69 CUGBP1 binds to CUG repeats within cTnT premRNA and regulates splicing of a single alternative exon that is included in embryonic striated muscle and skipped in the adult.67,70 Exon inclusion in embryonic striated muscle requires four intronic muscle-specific enhancers (MSEs) located upstream and downstream of the alternative exon . These elements are necessary and sufficient to promote exon inclusion of a heterologous exon in embryonic striated muscle. CUGBP1 binds directly to the conserved MSEs and promotes inclusion of an alternative exon (Fig. 3). Mutations in the MSEs that prevent CUGBP1 protein binding also prevent activation of exon inclusion by exogenous CUGBP1.66 Other alternatively spliced premRNAs potentially regulated by CUGBP1 or CUGBP1 homologous proteins include the neuron-specific and developmentally regulated exon 82 of GABAA. A CUGBP1 binding site has been mapped within the intron immediately upstream of the exon.71 Additionally, coexpression of CUGBP1 with an amyloid precursor protein (APP) minigene increased exon skipping of exon 8,72 suggesting that APP splicing might be regulated by CUGBP1 or CUGBP1 family members. The contribution of genes with disrupted splicing in DM1 pathology remains to be determined.

Significant amounts of CUGBP1 have been detected in cytoplasm, suggesting that CUGBP1 is involved in processing of RNAs in the cytoplasm as well as in nuclei. Investigations of the binding of CUGBP1 to a number of mRNAs showed that CUGBP1 binds to the 5' region of mRNA coding for the transcription factor C/EBPb. A single C/EBPb mRNA produces several protein isoforms (full-length protein and two truncated isoforms—liver inhibitor protein, LIP, and liver activator protein, LAP) via alternative initiation from downstream AUG codons.73 It has been found that CUGBP1 binds to the 5' region of C/EBPb mRNA and induces translation of the dominant negative molecule LIP.69 In agreement with observations obtained in tissue culture systems,65 an increase of CUGBP1 binding activity in DM1 patients also results in induction of LIP.65 Since overexpression of the LIP isoform alters cell proliferation,74 the increase of LIP levels in patients with DM1 suggests that proliferation rate might be also affected in DM1 disease.

Other Members of CUGBP1 Family

CUGBP1 is a member of a family of proteins called CUGBP1-like proteins or CELF proteins (CUGBP1 and ETR-3 like factors).70 This family also includes three other proteins called CELF3, CELF4, and CELF5.70 The CUGBP1 family has also been called BRUNOL because of their homology with the Drosophila bruno protein75 (Table 1). CUGBP1-like proteins are expressed in a tissue-specific manner. For example, CUGBP1 is widely expressed with high levels in skeletal muscle and heart,76 and ETR-3 is expressed in heart77 as well as in brain and striated muscle.70 This family is likely to function in multiple aspects of RNA processing and translation. CUGBP1 is closely related to the EDEN-binding protein (EDEN-BP) in Xenopus as well as bruno in Drosophila. Both of these proteins regulate translation by the interaction with specific elements within the 3' UTR of target mRNAs.78,79 ETR-3 protein was originally identified within human heart,80 and it is identical to a recently identified protein named apoptosis-related protein (APRP). APRP was identified as a differentially expressed gene in human neuroblastoma.81 Human ETR-3/APRP is abundant in cardiac tissue, suggesting that it might be involved in the regulation of cardiac-specific mRNAs. Analysis of RNA-binding activity of ETR-3 showed that, similar to CUGBP1, it binds to CUG repeats.77 It has been shown that ETR-3 is also capable of regulating the alternative splicing of cTnT70 and APP.72 It remains to investigate whether ETR-3 and other CUGBP1 homologous proteins are affected in DM1 patients. Since these proteins are expressed in a tissue-specific manner, it is possible that different members of this family function in different tissues, inducing tissue specific symptoms in DM1 disease.

Table 1. A family of CUGBP1 and ETR-3 like factors (CELF) bind to bruno element and regulate cTnT splicing.

Table 1

A family of CUGBP1 and ETR-3 like factors (CELF) bind to bruno element and regulate cTnT splicing.

EXP/MNBL Represent a Second Family of CUG Repeat Binding Proteins

Recently, another family of CUG binding proteins has been identified.82 Sequence analysis of these proteins, which bind to double-stranded RNA CUG repeats, indicated that they are putative human transcription factors that are homologous to the Drosophila muscle-blind protein.83 In Drosophila, muscle-blind protein is required for myogenic and photoreceptor differentiation, suggesting that EXPs in humans might be involved in skeletal muscle and eye development. In vitro analysis of EXP proteins by UV-cross link assay demonstrated that EXPs bind efficiently to expanded CUG repeat sequences.82 Although it is unknown whether EXP proteins also bind to long CUG expansion in vivo, these proteins could potentially be affected in DM1 by expansion of CUG repeats within the mutant DMPK mRNA. In agreement with this suggestion, immunofluorescence analysis of EXP in DM1 muscle cell line indicated formation of foci within DM1 myoblast nuclei.82 Further studies are required to investigate the function of EXPs, to find their native targets, and to determine DM1 symptoms, if any, that are associated with EXPs.


DM1 is one of the most complex diseases both at the clinical and molecular levels. Discovery of a CTG/CUG unstable expansion in the 3' UTR of the DM1 gene prompted researchers to investigate the biological effects of untranslated unstable elements on the structure of chromatin, efficiency of gene transcription, RNA processing, and signal transduction pathways. These studies provided knowledge that some of the main features of DM1 such as myotonia and testicular atrophy are due to expansion of RNA CUG repeats, while cardiac abnormalities and cataracts are associated with DMPK and SIX5 genes, respectively. While the details of each mechanism are being investigated, development of therapy is under way. For example, a trans-splicing ribozyme is able to shorten the CUG triplet repeat expansion within mutant RNA and repair it.84 Therefore, application of ribozymes for DM1 therapy is a perspective strategy to correct the dominant-negative effect of CUG repeats. Additional studies are required to understand the interaction and overlaps between pathological pathways induced by CTG/CUG repeat expansion in patient tissues.


The author's research is supported by grants from National Institutes of Health RO1AR44387 (LTT), RO3AG16392 (LTT), RO1AR45203 (SJT), RO1AR45653 (TAC) and grants from Muscular Dystrophy Association (LTT and TAC). DGM is a Lister Institute Research Fellow.


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