Alternative titles; symbols
HGNC Approved Gene Symbol: MMUT
Cytogenetic location: 6p12.3 Genomic coordinates (GRCh38): 6:49,430,360-49,463,253 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p12.3 | Methylmalonic aciduria, mut(0) type | 251000 | Autosomal recessive | 3 |
Methylmalonyl-CoA mutase (MUT) (EC 5.4.99.2) is a mitochondrial enzyme that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. MUT activity requires 5-prime-deoxyadenosylcobalamin (AdoCbl), a coenzyme form of vitamin B12.
By screening human placenta and liver cDNA libraries with an anti-MCM antibody, Ledley et al. (1988) isolated a partial MUT cDNA.
Jansen et al. (1989) isolated a full-length cDNA corresponding to the MUT gene from a human liver cDNA library. The deduced 742-amino acid protein has a molecular mass of 82.2 kD; the mature protein is 78.5 kD. The mitochondrial leader sequence comprises 32 amino acids.
Nham et al. (1990) determined that the MUT gene contains 13 exons spanning more than 35 kb.
Ledley et al. (1987) assigned the methylmalonyl-CoA mutase locus to chromosome 6p by use of a full-length MCM cDNA clone from a human liver cDNA library. By Southern blot analysis of DNA from human-hamster somatic cell hybrid cell lines, Ledley et al. (1988) assigned the MUT locus to 6p23-q12. By in situ hybridization, the locus was further localized to 6p21.2-p12. A highly informative RFLP was identified at the MCM gene locus.
By deletion mapping in cell lines with 6p deletions, Zoghbi et al. (1988) demonstrated that the MUT gene is located on 6p, proximal to GLO1 (138750). By use of a HindIII polymorphism identified by the MUT cDNA, they demonstrated the linkage relationships to HLA in reference CEPH families; the maximum lod score for MUT versus HLA was 3.04 at a recombination fraction of 0.28. Blanche et al. (1991) presented a genetic map of 6p which included RFLP mapping of the MUT locus.
By a study of recombinant inbred and congenic strains, Sertic et al. (1990) demonstrated that the mouse equivalent of the MUT gene is located on chromosome 17. Threadgill et al. (1990) assigned the gene to mouse chromosome 17 by in situ hybridization.
Ledley et al. (1990) could demonstrate no gross abnormalities of the MCM gene by Southern blot analysis in cell lines from patients with methylmalonic acidemia (MMA; see 251000). By other methods, however, they concluded that there are several independent alleles giving different levels of mRNA expression and biochemical phenotype of the cultured cells. The studies provided a molecular explanation for the wide phenotypic spectrum observed in the disorder.
In a patient with MMA mut(0), defined as having no residual enzyme activity, Jansen and Ledley (1990) identified compound heterozygosity for 2 mutations in the MUT gene (609058.0001 and 609058.0002).
In a patient with MMA mut(-), defined as having some residual enzyme activity, who had been reported by Ledley et al. (1990), Crane et al. (1992) identified a homozygous mutation in the MUT gene (609058.0005).
Crane and Ledley (1994) identified 4 novel mutations clustered near the C terminus of the MUT protein in patients with MMA. Three of the patients responded to cobalamin therapy. Each mutation showed interallelic complementation in cotransfection assays with clones bearing an R93H mutation (609058.0004). The findings suggested that the C-terminal region of the protein represents a cobalamin-binding domain. The location of this domain, as well as a pattern of sequence preservation between the homologous human and Propionobacterium shermanii enzymes, suggested a mechanism for interallelic complementation in which the cobalamin-binding defect is complemented in trans from the heterologous subunits of the dimer.
Drennan et al. (1996) made deductions concerning the molecular basis for dysfunction of some mutant forms of MCM by aligning the sequence of this gene with that of other B12-dependent enzymes, including the C-terminal portion of the cobalamin-binding region of methionine synthase (156570) from E. coli, the structure of which had been determined by x-ray crystallography. Previously identified mutants such as gly623-to-arg (609058.0008) were predicted to interfere with the structure and/or stability of the loop that carries histidine-627, the presumed lower axial ligand to the cobalt of adenosylcobalamin. A mutant such as gly703-to-arg (609058.0009), which maps to the binding site for the dimethylbenzimidazole nucleotide substituent of adenosylcobalamin, was predicted to block the binding of adenosylcobalamin because of the substitution of a large amino acid side chain for glycine.
Janata et al. (1997) identified 6 missense mutations producing amino acid changes in MUT cDNA from patients with mut(-) MMA. Two of the mutations had been reported in other patients. In 1 cell line, which the authors referred to as doubly heterozygous (compound heterozygous is the correct description), expression studies indicated that neither of the constituent mutant enzymes had a Km corresponding to the lower of the 2 estimated from the extract data. The finding was thought to reflect the natural occurrence of interallelic complementation in vivo in this cell line.
Adjalla et al. (1998) identified 7 novel mutations in mut methylmalonic aciduria and noted that 23 mutations had previously been identified.
Acquaviva et al. (2001) reported a novel MUT missense mutation, asn219 to tyr (N219Y; 609058.0010), in 5 unrelated families of French and Turkish descent from a population of 19 patients with MCM apoenzyme deficiency. All the patients exhibited a severe mut(0) methylmalonic acidemia phenotype, and 3 of them were homozygous for the N219Y mutation. The findings represented the first frequent MUT mutation reported in the Caucasian population.
Champattanachai et al. (2003) reported 2 novel mutations in a Thai patient with mut(0) methylmalonic acidemia.
Acquaviva et al. (2005) analyzed a cohort of 40 MCM-deficient patients with MMA affected by either the mut(0) or mut(-) form of the disease. By direct sequencing of cDNA and genomic DNA of the MUT gene, they detected 42 mutations, 29 of which were novel. These included 5 frameshift mutations (insertion, deletion, or duplication of a single nucleotide), 5 sequence modifications in consensus splice sites, 6 nonsense and 12 missense mutations, and a large genomic deletion including exon 12. They explored how the 12 novel missense mutations might cause the observed phenotype by mapping them onto a 3-dimensional model of the human MCM generated by homology with the enzyme in P. shermanii. Acquaviva et al. (2005) increased the number of mutations in the MUT gene to 84 and discussed their prevalence and distribution throughout the coding sequence in relation to enzyme structure. The authors noted that most of the mutations in the MUT gene are private, with no demonstrated hotspots. Prior to their study only 2 recurrent mutations had been described: glu 117 to ter (E117X; 609058.0006) and N219Y, which had high frequencies in Japanese and Caucasian populations, respectively. Acquaviva et al. (2005) confirmed a high frequency of N219Y in Caucasians: 12 of their 40 patients carried the mutation in a heterozygous or homozygous state, which represented 19% of the alleles tested.
Worgan et al. (2006) sequenced the MUT gene in 160 patients with mut MMA. Mutations were identified in 96% of disease alleles. Mutations were distributed through all coding exons, but predominantly in exons 2, 3, 6, and 11. A total of 116 different mutations, 68 of which were novel, were identified; 53% were missense mutations, 22% deletions, duplications or insertions, 16% were nonsense mutations, and 9% were splice site mutations. Sixty-one of the mutations were identified in only 1 family. A novel mutation in exon 2, R108C (609058.0011), was identified in 16 of 27 Hispanic patients. SNP genotyping data demonstrated that Hispanic patients with this mutation shared a common haplotype. Three other mutations were seen exclusively in Hispanic patients. Seven mutations were seen almost exclusively in black patients, including the G717V mutation (609058.0005), which was identified in 12 of 29 black patients. Two mutations were seen only in Asian patients. Some frequently identified mutations were not population-specific and were identified in patients of various ethnic backgrounds. Some of these mutations were found in mutation clusters in exons 2, 3, 6, and 11, suggesting that they represented recurrent mutations.
Rincon et al. (2007) described 3 genomic alterations--1 in the MUT gene, 1 in the PCCA gene (232000), and 1 in the PCCB gene (232050)--that were responsible for aberrant insertion of intronic sequences in patients' mRNA. The authors targeted the aberrant intronic pseudoexons with antisense morpholino oligonucleotides (AMOs) that prevented aberrant splicing, thus generating normal mRNA which was translated into functional protein, achieving therapeutic correction of the defect in methylmalonic acidemia (251000) or propionic acidemia (606054). No effect on MCM activity was obtained after AMO treatment in cell lines bearing different mutations and exhibiting some levels of intronic MUT insertions. Rincon et al. (2007) suggested that this therapeutic strategy would be potentially applicable to a large number of cases with deep intronic changes that remained undetected by standard mutation-detection techniques at that time. The major issues facing clinical applications of morpholino analogs of oligonucleotides concerned safe delivery and optimal dose determination for each tissue involved. Efficient and nontoxic delivery of AMO to the liver, which would be the target tissue in this disorder, was one major challenge to be overcome before the practical use of AMO in patients with methylmalonic acidemia could be envisaged. In Duchenne muscular dystrophy (310200), antisense oligonucleotides have been administered intravenously, achieving splicing modulation to restore the coding frame for dystrophin (Takeshima et al., 2006). The efficacy of antisense therapeutics for splicing correction must be determined in each disease model and for each deleterious splicing event.
To understand the pathologic mechanisms leading to MMA, Forny et al. (2014) assessed stability and enzymatic effects of 23 MMUT missense mutations expressed in 2 recombinant expression systems. All 23 mutants had decreased enzymatic function. Stability was assessed based on thermolability and folding of the mutant protein. Six mutations led to abnormal folding, and 4 others led to increased thermolability. In evaluating enzymatic defects in the MMUT mutants, 4 mutations led to isolated Km defects, and 6 mutations led to isolated catalytic defects. Three mutations led to increased Km and thermolability, 1 mutation led to catalytic dysfunction and thermolability, and 3 mutations led to both folding and catalytic defects. Forny et al. (2014) then tested whether osmolytes could stabilize the mutant proteins and found that soluble protein yield was increased with glycerol or TMAO in some mutants.
Using 3D organotypic brain cell cultures derived from embryos of a brain-specific Mut -/- mouse, Remacle et al. (2018) investigated mechanisms leading to brain damage in methylmalonic aciduria. The in vitro model was challenged with the catabolic stress of temperature shift. Remacle et al. (2018) found typical metabolites for methylmalonic aciduria as well as a massive ammonia increase in the media of mutant mouse brain cultures. Investigation of pathways involved in intracerebral ammonia production revealed increased expression of glutaminase-2 (GLS2; 606365) and diminished expression of glutamate dehydrogenase-1 (GLUD1; 138130) in Mut -/- aggregates. Astrocytes showed swollen fibers and cell bodies, and oligodendrocytes showed inhibited axonal elongation and delayed myelination. Most effects were even more pronounced after 48 hours at 39 degrees C. Microglia activation and an increased apoptosis rate suggested degeneration of Mut -/- brain cells.
Fenton et al. (1987) identified a mutation in the MUT gene that appeared to represent an amino-terminal deletion that removed the leader peptide necessary for proper uptake and cleavage of the precursor. Ledley et al. (1990) identified a C-to-T transition in the MUT gene, resulting in a gln17-to-ter (Q17X) substitution in the mitochondrial leader sequence of the protein as a cause of mut(0) MMA (251000). Cells carrying this mutation produced immunoreactive protein translated from AUG codons downstream from the termination codon and, therefore, lack a mitochondrial leader peptide.
In an infant with mut(0) MMA (251000), Jansen and Ledley (1990) identified compound heterozygosity for 2 mutations in the MUT gene: a 389T-C transition, resulting in a trp105-to-arg (W105R) substitution, and a 1206C-A transversion, resulting in an ala378-to-glu substitution (A378E; 609058.0003).
For discussion of the ala378-to-glu (A378E) mutation in the MUT gene that was found in compound heterozygous state in a patient with mut(0) methylmalonic aciduria (251000) by Jansen and Ledley (1990), see 609058.0002.
In skin fibroblasts derived from a patient with neonatal methylmalonic aciduria (251000) who died at the age of 5 months, Raff et al. (1991) identified a 354G-A transition in the MUT gene, resulting in an arg93-to-his (R93H) substitution. Cell-fusion complementation analysis showed complementation with 4 out of 5 mut(-) lines and 3 out of 9 mut(0) lines, suggesting interallelic complementation.
Ledley and Rosenblatt (1997) noted most of the MUT mutations that complement R93H are located in a common region near the C terminus of the protein, suggesting that these mutations complement a discrete function required for activity of the R93H protein. Mutations exhibiting complementation with R93H include G623R (609058.0008) and G703R (609058.0009) among the mut(0) cell lines, and G717V (609058.0005) among the mut(-) cell lines.
In a patient with a mut(-) MMA (251000) phenotype previously characterized by Ledley et al. (1990), Crane et al. (1992) identified 3 novel base changes in the MUT gene. They concluded that the particular phenotype was due to a homozygous gly717-to-val (G717V) substitution, which resulted in an unstable enzyme. This mutation showed interallelic complementation with the R93H mutation (609058.0004). The patient was also homozygous also 2 other mutations which were presumably neutral: his532-to-arg (H532R) and val671-to-ile (V671I). Crane et al. (1992) compared the phenotype in the original patient and in 2 others with the G717V mutation. All 3 presented in the first years of life with multiple episodes of life-threatening organic acidosis and hyperammonemia. None had evidence of disease in the perinatal period, and all 3 were of low-normal intelligence. The authors concluded that the phenotype was intermediate between the fulminant and benign forms of methylmalonic aciduria, and suggested that the level of residual MUT enzyme activity associated with the G717V mutation may be close to the threshold required in vivo for maintaining metabolic homeostasis.
In a mutation screen of 160 patients with mut MMA, Worgan et al. (2006) found the G717V mutation in 12 of 29 black patients.
Ogasawara et al. (1994) identified 2 novel mutations in the MUT gene, 1 of which was prevalent among Japanese patients with mut(-) MMA (251000). One patient was homozygous for a 425G-T transversion resulting in a glu117-to-ter (E117X) substitution. The E117X mutation was accompanied by instability of MCM mRNA, the first report of such a mutation.
In a Japanese patient with MMA mut(-) (251000), Ogasawara et al. (1994) found compound heterozygosity for 2 mutations in the MUT gene: the E117X mutation (609058.0006) frequent in Japanese patients and a 2-bp deletion (769delCA), resulting in a frameshift and premature termination. The termination occurred 508 amino acids upstream of the C-terminus of the protein.
In an African American male infant with MMA mut(0) (251000), Qureshi et al. (1994) identified compound heterozygosity for 2 mutations in the MUT gene: gly623-to-arg (G623R) and gly703-to-arg (G703R; 609058.0009). Cotransfection of each mutation with the R93H mutation mutation (609058.0004) stimulated propionate uptake, indicating that both mutations were independently capable of complementing the R93H mutation, whereas the G717V mutation (609058.0005) did not complement the G623R cell line. Qureshi et al. (1994) found that the MUT mutations identified in cell lines that exhibit intragenic complementation to G623R do not exhibit any specific pattern of charge or amino acid structure. Furthermore, neither the mut(0) versus mut(-) phenotype nor intragenic complementation could be predicted by the relative primary amino acid position.
For discussion of the gly703-to-arg (G703R) mutation in the MUT gene that was found in compound heterozygous state in a patient with mut(0) methylmalonic aciduria (251000) by Qureshi et al. (1994), see 609058.0008.
In 5 unrelated patients with MMA mut(0) (251000), Acquaviva et al. (2001) identified a 731A-T transversion in the MUT gene, resulting in an asn219-to-tyr (N219Y)in a conserved codon from bacteria to mouse and man. Mapping of the mutation onto a 3-dimensional model of human MCM suggested impaired folding and/or poor stability compatible with the mut(0) phenotype. Functional expression studies showed loss of enzyme activity. Three of the patients were homozygous for the N219Y mutation and 2 patients were compound heterozygous. The 5 patients were of French or Turkish descent, from a population of 19 patients with MCM apoenzyme deficiency, and the N219Y mutation represented 21% of the MUT alleles screened. Further screening for this mutation in 205 French children revealed 2 carriers, suggesting that N219Y is a frequent mutation in the French population and that the incidence of MMA might be underestimated.
The high frequency of N219Y in Caucasians was confirmed by the study of Acquaviva et al. (2005), who found that this allele represented 19% of the alleles tested among 40 European patients. Berger et al. (2001) detected the N219Y mutation in homozygous state in 2 of 7 Arab Muslim patients, suggesting that this mutation may also be frequent in this ethnic group.
In a screen of the MUT gene in 160 patients with mut MMA (251000), Worgan et al. (2006) found a novel mutation in exon 2, 322C-T (arg108 to cys, R108C), in 16 of 27 Hispanic patients. SNP phenotyping data demonstrated that Hispanic patients with this mutation shared a common haplotype.
Cavicchi et al. (2006) performed genetic and biochemical prenatal diagnosis at 11 weeks' gestation in a family with a proband affected by MMA (251000) due to homozygosity for a 643G-A transition in the MUT gene resulting in a gly215-to-ser substitution (G215S). Both chorionic villus and amniotic fluid samples were used. The presence of high levels of methylmalonic acid and propionylcarnitine determined by gas chromatography/mass spectrometry and tandem mass spectrometry analysis, respectively, and the identification of the G215S mutation in homozygosity in fetal DNA allowed a certain, rapid, and early diagnosis.
Rincon et al. (2007) studied a patient with mut MMA (251000) who had been found by Martinez et al. (2005) to have a 76-bp insertion between exons 11 and 12 corresponding to an exon-like region in intron 11 (1957ins76). Rincon et al. (2007) found that the patient's DNA contained a C-to-A change in intron 11 at position +7 relative to the inserted sequence (IVS11-891C-A). Experimental confirmation that the change was pathogenic and caused the activation of the pseudoexon was obtained by use of a minigene. Rincon et al. (2007) used antisense morpholino oligonucleotides (AMOs) to target a cryptic splice site to block access of the splicing machinery in the pseudoexonic region in the pre-mRNA. Using this antisense therapeutics, they obtained correctly spliced mRNA that was effectively translated, and methylmalonyl CoA mutase (MCM) activity was rescued in the patients' fibroblasts. The effect of the AMO was sequence- and dose-dependent. Close to 100% of MCM activity, measured by incorporation of (14)C-propionate, was obtained after 48 hours, and correctly spliced MUT mRNA was still detected 15 days after treatment. The patient with MUT deficiency studied by Rincon et al. (2007) was compound heterozygous for the intronic insertion and a splicing mutation in the last nucleotide of exon 10 (1808G-A; 609058.0014), and had 2 aberrant transcripts as a result of the use of cryptic splice sites.
For discussion of the splice site mutation in the MUT gene (1808G-A) that was found in compound heterozygous state in a patient with mut MMA (251000) by Rincon et al. (2007), see 609058.0013.
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