HGNC Approved Gene Symbol: MMACHC
SNOMEDCT: 74653006;
Cytogenetic location: 1p34.1 Genomic coordinates (GRCh38) : 1:45,500,300-45,513,382 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.1 | Methylmalonic aciduria and homocystinuria, cblC type | 277400 | Autosomal recessive | 3 |
Lerner-Ellis et al. (2006) identified a gene, designated MMACHC, within the critical interval on chromosome 1p34-p32 for methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400). The cDNA had an 846-basepair open reading frame encoding a 282-amino acid polypeptide with a predicted molecular weight of 31.7 kD. Northern blot analysis detected expression of 1.9-, 3.0-, and 5.4-kb transcripts in most human tissues examined, with higher levels in fetal liver and lower levels in spleen, lymph node, thymus, and bone marrow. The 3.0-kb message predominated, followed by the 5.4- and 1.9-kb messages. Lerner-Ellis et al. (2006) stated that MMACHC is not a member of any previously identified gene family. The protein is well conserved among mammals, although the C-terminal end does not seem to be conserved in eukaryotes outside Mammalia. While no homologous protein was identified in prokaryotes, motifs homologous to those found in bacterial genes with cobalamin-related functions were identified. Transduction of wildtype MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicted that the C-terminal region of the product of the MMACHC gene folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake.
The MMACHC gene contains 5 exons (Lerner-Ellis et al., 2006).
Lerner-Ellis et al. (2006) identified the MMACHC gene on chromosome 1p34.1, within the locus for methylmalonic aciduria and homocystinuria cblC type.
In 204 individuals with methylmalonic aciduria (MMA) and homocystinuria cblC type (MAHCC; 277400), Lerner-Ellis et al. (2006) found 42 different mutations, many consistent with loss of function of the protein product. One mutation, 271dupA (609831.0001), accounted for 40% of all disease alleles.
Among 79 unrelated Chinese patients with combined methylmalonic aciduria and homocystinuria cblC type, Liu et al. (2010) identified 24 different mutations in the MMACHC gene, including 7 novel mutations. All patients had 2 mutations, except for 3 patients in whom only 1 mutation was identified. The 2 most common alleles were W203X (609831.0006) and 658delAAG (609831.0007), which accounted for 48.1% and 13.9% of mutant alleles, respectively. Haplotype analysis indicated a different founder effect for each mutation, but the major mutation profile did not differ between patients from northern and southern China.
In 4 patients with combined pulmonary arterial hypertension and renal thrombotic microangiopathy, Komhoff et al. (2013) detected 1 of 2 basepair substitutions at nucleotide 276 of the MMACHC gene (see 609831.0008 and 609831.0009). These patients were compound heterozygous for various frameshift mutations. A fifth patient had a homozygous missense mutation in MMACHC (609831.0010). Komhoff et al. (2013) identified cblC deficiency as the cause of the rare combination of pulmonary arterial hypertension and renal thrombotic microangiopathy in these patients. The authors proposed that early recognition of cblC deficiency and vigorous treatment with hydroxocobalamin may ameliorate the devastating course of this condition.
In 3 unrelated patients with autosomal recessive cblC vitamin B12 deficiency, Gueant et al. (2018) identified compound heterozygous mutations in the MMACHC gene: a different coding mutation on 1 allele in all 3 patients (609831.0011-609831.0013), combined with the same 'secondary epimutation' on the other allele. The epimutation, 32 hypermethylated CpG sites detected by bisulfite sequencing, was a consequence of a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene: c.515-1G-T (176763.0001) or c.515-2A-T (176763.0002). The PRDX1 mutations were also found in unaffected relatives who carried the secondary epimutation. In all instances, the PRDX1 mutations affected a canonical splice acceptor site of intron 5 and caused skipping of exon 6 and the polyA termination signal of PRDX1. The resulting read-through transcript extended through the adjacent MMACHC locus in the antisense orientation. The authors proposed that the antisense transcript leads to the formation of triplexes in the promoter of MMACHC and generates CpG methylation resulting in reduced expression of the normal message. This was confirmed experimentally by growing fibroblasts from an affected proband in 5-azacytidine, which reduced promoter methylation, and by silencing PRDX1 with an siRNA, both of which increased expression of MMACHC.
By Sanger or next-generation sequencing in 70 Chinese individuals with MAHCC and hydrocephalus, He et al. (2020) identified homozygous or compound heterozygous mutations in the MMACHC gene. The parents in each case were carriers of the mutation. Eighteen individual mutations were identified, including 4 novel mutations (Q143X, W200X, Y205X, and c.568insT) that were predicted to cause loss of function and were not present in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases. The most frequent mutation was W209X (609831.0006), accounting for 62.9% of the mutations, followed by c.658delAAG (609831.0007), R73X, and c.567dupT, seen at a frequency of 12.1%, 5%, and 5%, respectively. The findings were consistent with a previous study in the Chinese population by Liu et al. (2010).
In a 28-year-old woman with nonsyndromic bull's eye maculopathy who was subsequently diagnosed with cblC, Collison et al. (2015) identified compound heterozygous mutations in the MMACHC gene (609831.0005 and 609831.0011). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The parents were shown to be mutation carriers.
Morel et al. (2006) reported genotype-phenotype correlations in 37 patients from published case reports, representing most of the landmark descriptions of cobalamin C deficiency. Twenty-five of 37 had early-onset disease, presenting in the first 6 months of life. Seventeen of these 25 were found to be either homozygous for the 271dupA mutation (609831.0001) (n = 9) or for the 331C-T (R111X; 609831.0004) mutation (n = 3) or compound heterozygous for these 2 mutations (n = 5). Nine of 12 late-onset cases presented with acute neurologic symptoms; 4 of 9 were homozygous for the 347T-C mutation (609831.0002), 2 of 9 were compound heterozygous for the 271dupA and 394C-T (R132X; 609831.0003) mutations, and 3 of 9 for the 271dupA mutation and a missense mutation. The 394C-T mutation is common in the Asiatic-Indian/Pakistani/Middle Eastern populations.
Among 118 patients with cblC deficiency, Lerner-Ellis et al. (2009) identified 34 different MMACHC mutations, including 11 novel mutations. The 271dupA mutation was the most common, accounting for 42% of pathogenic alleles, followed by the R132X (20%) and R111X (5%) mutations. Six variants defined specific haplotypes that varied with ethnicity. Genotype/phenotype correlations were apparent. Individuals with the R132X and R161Q (609831.0005) mutations tended to present with late-onset disease, whereas patients with R111X and 271dupA mutations tended to present in infancy. Functional expression analyses on cblC fibroblasts showed that the early-onset 271dupA mutation was consistently underexpressed compared to control alleles and the late-onset R132X and R161Q mutations. The early-onset R111X mutation was also underexpressed when compared to control alleles and the R132X mutation. Quantitative RT-PCR studies showed that the late-onset R132X mutation had significantly higher levels of transcript compared to cell lines homozygous for the early-onset mutations.
Demaret et al. (2024) compared the phenotypes of 3 patients who were compound heterozygous for mutations in the MMACHC gene, c.271dupA (609831.0001) and L53P (609831.0013), and 4 patients who were homozygous for the c.271dupA mutation. The patients with compound heterozygous mutations had milder disease manifestations compared to the patients with the homozygous mutations. The patients with compound heterozygous mutations had normalization of homocysteine and methylmalonic acid levels with hydroxocobalamin treatment, age-appropriate cognitive development, and normal eye examinations, whereas the patients with homozygosity for the c.271dupA mutation had psychomotor retardation, ophthalmologic abnormalities, and feeding difficulties. Fibroblasts from the patients with compound heterozygous mutations exhibited higher propionate incorporation compared to fibroblasts from the patients with the homozygous mutation.
In individuals from several different ethnic groups, Lerner-Ellis et al. (2006) found that methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400) was associated with a 271dupA mutation in the MMACHC gene. The 271dupA mutation predicts a change of amino acid residue 91 from arginine to lysine followed by frameshift with a premature termination 14 codons downstream (Arg91LysfsTer14). The mutation was present in homozygous state in 46 individuals, in whom the diagnosis was made under the age of 1 year in 44. In 2 individuals in whom the diagnosis was made after the age of 20 years, the 271dupA mutation was in compound heterozygous state with a 347T-C transition (609831.0002). The 271dupA mutation accounted for 40% of all disease alleles among the 204 patients studied.
Lerner-Ellis et al. (2009) identified the 271dupA allele in 42% of pathogenic alleles from 118 patients with cblC. Patients with the 271dupA mutation tended to present in infancy. Transcript analysis on cblC fibroblasts showed that the early-onset 271dupA mutation was consistently underexpressed compared to control alleles and to MMACHC alleles associated with later-onset disease.
In 2 patients in whom the diagnosis of methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400) was made after the age of 20 years, Lerner-Ellis et al. (2006) found compound heterozygosity in the MMACHC gene for the most common mutation, 271dupA (609831.0001), which in homozygous state causes early-onset disease, and a 347T-C transition, which was predicted to result in a leu116-to-pro (L116P) substitution.
In a survey of 204 individuals with methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400), Lerner-Ellis et al. (2006) found 34 examples of the 394C-T mutant allele of the MMACHC gene, predicted to result in an arg132-to-ter mutation (R132X). The R132X mutation was primarily associated with late-onset disease and was noted in the homozygous state among published individuals in Asiatic-Indian, Pakistani, or Middle Eastern descent and reported by Morel et al. (2006) in an additional 9 unpublished patients from their database who were either of Asiatic-Indian, Pakistani, or Middle Eastern descent.
Ben-Omran et al. (2007) reported 2 unrelated girls of Pakistani and Bengali origin, respectively, with cblC disease caused by a homozygous R132X mutation. The girls presented with neuropsychiatric symptoms at ages 14 and 10 years, respectively.
In a study of 118 patients with cblC disease, Lerner-Ellis et al. (2009) found that individuals with the R132X mutation tended to present with late-onset disease. Transcript and RT-PCR analysis of cblC fibroblasts showed that the R132X mutation resulted in significantly higher levels of transcript compared to cell lines homozygous for the early-onset mutations. The authors postulated that nonsense-mediated decay may not occur with this mutation, or that it may occur to a lesser extent. Alternatively, the mutation may result in a truncated protein with residual function. Lerner-Ellis et al. (2009) identified the R132X mutation in 20% of pathogenic alleles from 118 patients with cblC.
In a review of 37 published cases of methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400), Morel et al. (2006) identified 3 Cajun patients who were homozygous for a 331C-T transition in the MMACHC gene, resulting in an arg111-to-ter (R111X) substitution. They also reported 3 unpublished patients of French Canadian background who were homozygous for this mutation.
Lerner-Ellis et al. (2009) identified the R111X mutation in 5% of pathogenic alleles from 118 patients with cblC. Patients with the R111X mutation tended to present in infancy. Functional expression analyses on cblC fibroblasts showed that the early-onset R111X mutation was underexpressed when compared to control alleles or to alleles associated with late-onset disease.
In a male with late-onset methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400), originally reported by Bodamer et al. (2001), Morel et al. (2006) identified compound heterozygosity for 2 mutations in the MMACHC gene: the 271dupA (609831.0001) mutation and a 482G-A transition resulting in an arg161-to-gln (R161Q) substitution.
Tsai et al. (2007) described a 36-year-old woman with a psychiatric history and a spinal cord infarct who was subsequently diagnosed with methylmalonic aciduria and homocystinuria cblC type. Molecular analysis of the MMACHC gene revealed compound heterozygosity for the 271dupA and R161Q mutations.
Among 118 patients with cblC, Lerner-Ellis et al. (2009) found that those with the R161Q mutation tended to present with late-onset disease.
Liu et al. (2010) also found that the R161Q mutation was associated with a late onset and relatively mild phenotype among Chinese patients with cblC carrying this mutation. This allele was the third most common mutation found among 79 unrelated patients, accounting for 7% of mutant alleles.
In a 28-year-old woman with nonsyndromic bull's eye maculopathy who was subsequently diagnosed with cblC, Collison et al. (2015) identified compound heterozygous mutations in the MMACHC gene: R161Q and a 1-bp insertion (c.270_271insA; 609831.0011), predicted to result in a frameshift and a premature termination codon (Arg91LysfsTer14). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The parents were shown to be mutation carriers.
In Chinese patients with methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400), Liu et al. (2010) identified a 609G-A transition in exon 4 of the MMACHC gene, resulting in a trp203-to-ter (W203X) substitution. This allele was the most common mutation found among 79 unrelated patients, accounting for 48.1% of mutant alleles. Fifteen patients who were homozygous for the mutation showed an early-onset phenotype, with 3 showing onset before age 4 years. Haplotype analysis suggested a founder effect.
In a molecular analysis of 70 Chinese individuals with MAHCC, He et al. (2020) found that the W203X mutation accounted for 62.9% of the identified mutations. Twenty-nine patients were homozygous for the mutation.
In Chinese patients with methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400), Liu et al. (2010) identified a 3-bp deletion (658delAAG) in exon 4 of the MMACHC gene, resulting in an in-frame deletion of lys220. This allele was the second most common found among 79 unrelated patients, accounting for 13.9% of mutant alleles. Haplotype analysis suggested a founder effect.
In a molecular analysis of 70 Chinese individuals with MAHCC, He et al. (2020) found that the 658delAAG mutation accounted for 12.1% of the identified mutations.
In 3 patients with combined pulmonary arterial hypertension and renal thrombotic microangiopathy caused by cblC deficiency (MAHCC; 277400), Komhoff et al. (2013) identified compound heterozygosity for a c.276G-T transversion in the MMACHC gene, resulting in a glu92-to-asp (E92D) substitution. Two patients also carried the common 271dupA (609831.0001) mutation on the other allele; the third patient was compound heterozygous for a different frameshift mutation. The patients were of Spanish/Turkish or Dutch ethnicity. Because another patient with a synonymous change at that position was identified (see 609831.0009), the authors concluded that the actual effect of the mutation, which affects the last nucleotide of exon 2, is aberrant splicing and ultimately deletion of the erroneous pre-mRNA via nonsense-mediated decay.
In an Italian patient with combined renal thrombotic microangiopathy and pulmonary arterial hypertension caused by cblC deficiency (MAHCC; 277400), Komhoff et al. (2013) identified heterozygosity for a c.276G-A transition in the MMACHC gene, resulting in a synonymous glu92-to-glu (E92E) substitution. Because this mutation occurred in the last nucleotide of exon 2, the authors suggested that the actual effect of the mutation is an aberrantly spliced pre-mRNA that undergoes nonsense-mediated decay. The patient was heterozygous for a frameshift mutation on the other allele.
Komhoff et al. (2013) reported a patient of Dutch ancestry with combined renal thrombotic microangiopathy and pulmonary arterial hypertension caused by cblC deficiency (MAHCC; 277400) who had a homozygous c.464G-A transition in the MMACHC gene, resulting in a gly155-to-glu (G155E) substitution. The patient presented at 2.5 years of age and died from right ventricular failure 2 weeks after diagnosis. Homocysteine level was 123 micromol/L; methylmalonic acid (MMA) was 14,424 nmol/L.
In a Caucasian female (CHU-12122) with cbl-type methylmalonic aciduria and homocystinuria (MAHCC; 277400), who died at 1 month of age, Gueant et al. (2018) identified compound heterozygous mutations in the MMACHC gene: a 1-bp insertion (c.270_271insA), resulting in a frameshift and a premature termination codon (Arg91LysfsTer14), inherited from the mother, and a secondary epimutation causing promoter hypermethylation and MMACHC silencing inherited from the father. The secondary epimutation was triggered by a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene (176763.0001). The patient's paternal grandfather also carried the epimutation, which was present in her father's sperm.
For discussion of the c.270_271insA mutation that was found in compound heterozygous state in the MMACHC gene in a patient with MAHCC by Collison et al. (2015), see 609831.0005.
In a female (WG-3838) of Japanese and Korean ancestry, who died at 2 months of age, with cbl-type methylmalonic aciduria and homocystinuria (MAHCC; 277400), Gueant et al. (2018) identified compound heterozygous mutations in the MMACHC gene: a splice site mutation (c.81G-A) inherited from the mother, and a secondary epimutation causing promoter hypermethylation and MMACHC silencing inherited from the father. The secondary epimutation was triggered by a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene (176763.0002).
In a 59-year-old Caucasian man (WG-4152) with cbl-type methylmalonic aciduria and homocystinuria (MAHCC; 277400), Gueant et al. (2018) identified compound heterozygous mutations in the MMACHC gene: a c.158T-C transition, resulting in a leu53-to-pro (L53P) substitution, and a secondary epimutation causing promoter hypermethylation and MMACHC silencing. The secondary epimutation was triggered by a heterozygous mutation in the adjacent, reverse-oriented PRDX1 gene (176763.0001).
Ben-Omran, T. I., Wong, H., Blaser, S., Feigenbaum, A. Late-onset cobalamin-C disorder: a challenging diagnosis. Am. J. Med. Genet. 143A: 979-984, 2007. [PubMed: 17431913] [Full Text: https://doi.org/10.1002/ajmg.a.31671]
Bodamer, O. A. F., Rosenblatt, D. S., Appel, S. H., Beaudet, A. L. Adult-onset combined methylmalonic aciduria and homocystinuria (cblC). Neurology 56: 1113 only, 2001. [PubMed: 11320193] [Full Text: https://doi.org/10.1212/wnl.56.8.1113]
Collison, F. T., Xie, Y., Gambin, T., Jhangiani, S., Muzny, D., Gibbs, R., Lupski, J. R., Fishman, G. A., Allikmets, R. Whole exome sequencing identifies an adult-onset case of methylmalonic aciduria and homocystinuria type C (cblC) with non-syndromic bull's eye maculopathy. Ophthal. Genet. 36: 270-275, 2015. [PubMed: 25687216] [Full Text: https://doi.org/10.3109/13816810.2015.1010736]
Demaret, T., Bedard, K., Soucy, J. F., Watkins, D., Allard, P., Levtova, A., O'Brien, A., Brunel-Guitton, C., Rosenblatt, D. S., Mitchell, G. A. The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients. Molec. Genet. Metab. 142: 108345, 2024. [PubMed: 38387306] [Full Text: https://doi.org/10.1016/j.ymgme.2024.108345]
Gueant, J.-L., Chery, C., Oussalah, A., Nadaf, J., Coelho, D., Josse, T., Flayac, J., Robert, A., Koscinski, I., Gastin, I., Filhine-Tresarrieu, P., Pupavac, M., and 19 others. A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients. Nature Commun. 9: 67, 2018. Note: Electronic Article. Erratum: Nature Commun. 9: 554, 2018. [PubMed: 29302025] [Full Text: https://doi.org/10.1038/s41467-017-02306-5]
He, R., Zhang, H., Kang, L., Li, H., Shen, M., Zhang, Y., Mo, R., Liu, Y., Song, J., Chen, Z., Liu, Y., Jin, Y., and 11 others. Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency. Neurology 95: e3129-e3137, 2020. Note: Electronic Article. [PubMed: 32943488] [Full Text: https://doi.org/10.1212/WNL.0000000000010912]
Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F. Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency. Pediatrics 132: e540-e544, 2013. Note: Electronic Article. [PubMed: 23837176] [Full Text: https://doi.org/10.1542/peds.2012-2581]
Lerner-Ellis, J. P., Anastasio, N., Liu, J., Coelho, D., Suormala, T., Stucki, M., Loewy, A. D., Gurd, S., Grundberg, E., Morel, C. F., Watkins, D., Baumgartner, M. R., Pastinen, T., Rosenblatt, D. S., Fowler, B. Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Hum. Mutat. 30: 1072-1081, 2009. [PubMed: 19370762] [Full Text: https://doi.org/10.1002/humu.21001]
Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006. [PubMed: 16311595] [Full Text: https://doi.org/10.1038/ng1683]
Liu, M.-Y., Yang, Y.-L., Chang, Y.-C., Chiang, S.-H., Lin, S.-P., Han, L.-S., Qi, Y., Hsiao, K.-J., Liu, T.-T. Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria. J. Hum. Genet. 55: 621-626, 2010. [PubMed: 20631720] [Full Text: https://doi.org/10.1038/jhg.2010.81]
Morel, C. F., Lerner-Ellis, J. P., Rosenblatt, D. S. Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations. Molec. Genet. Metab. 88: 315-321, 2006. [PubMed: 16714133] [Full Text: https://doi.org/10.1016/j.ymgme.2006.04.001]
Tsai, A. C.-H., Morel, C. F., Scharer, G., Yang, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Thomas, J. A. Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance. Am. J. Med. Genet. 143A: 2430-2434, 2007. [PubMed: 17853453] [Full Text: https://doi.org/10.1002/ajmg.a.31932]