Alternative titles; symbols
HGNC Approved Gene Symbol: MMADHC
Cytogenetic location: 2q23.2 Genomic coordinates (GRCh38): 2:149,569,637-149,587,775 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q23.2 | Homocystinuria, cblD type, variant 1 | 277410 | Autosomal recessive | 3 |
| Methylmalonic aciduria and homocystinuria, cblD type | 277410 | Autosomal recessive | 3 | |
| Methylmalonic aciduria, cblD type, variant 2 | 277410 | Autosomal recessive | 3 |
Vitamin B12 (cobalamin) is an essential cofactor in several metabolic pathways. Intracellular conversion of cobalamin to adenosylcobalamin in mitochondria and to methylcobalamin in cytoplasm is necessary for homeostasis of methylmalonic acid and homocysteine. The MMADHC gene encodes a protein involved in an early step of cobalamin metabolism (Coelho et al., 2008).
By RT-PCR of fibroblast mRNA, Coelho et al. (2008) obtained a full-length cDNA for C2ORF25. The deduced 296-amino acid protein has a calculated molecular mass of 32.8 kD. It has an N-terminal mitochondrial leader sequence and a putative vitamin B12-binding motif, NxHxxG, at residues 81 through 86. EST database analysis suggested that C2ORF25 is highly expressed in most tissues.
Coelho et al. (2008) determined that the C2ORF25 gene contains 8 exons and spans about 18 kb.
By genomic sequence analysis, Coelho et al. (2008) mapped the C2ORF25 gene to chromosome 2q23.2.
Coelho et al. (2008) identified biallelic mutations in the C2ORF25 gene in 7 patients with cblD patients with homocystinuria (see 277410) (611935.0001-611935.0003), methylmalonic aciduria (611935.0004-611935.0006), and combined homocystinuria and methylmalonic aciduria (MAHCD; 611935.0007-611935.0009). Some of the patients had previously been reported by Goodman et al. (1970), Cooper et al. (1990), and Suormala et al. (2004). In vitro functional expression studies showed that wildtype C2ORF25 rescued individual mutant cellular phenotypes. There appeared to be some correlation between biochemical phenotype and location of the mutation: those with methylmalonic aciduria had mutations toward the N terminus, whereas those with homocystinuria and the combined biochemical phenotype had mutations toward the C terminus.
Stucki et al. (2012) studied the effect of various MMADHC constructs on protein function in cell lines. For example, mutant alleles associated with the cblD-homocystinuria (HC) phenotype were unable to rescue MeCbl synthesis, whereas mutant alleles associated with the cblD-methylmalonic aciduria (MMA) phenotype could restore MeCbl synthesis. In combined cblD-MMA/HC cells, improving mitochondrial targeting of MMADHC increased the formation of AdoCbl with a concomitant decrease in MeCbl formation. In cblD-MMA cells, this effect was dependent on the mutation and showed a negative correlation with endogenous MMADHC mRNA levels. The findings supported the hypothesis that the MMADHC protein contains various domains for targeting the protein towards the mitochondria, MeCbl synthesis, and AdoCbl synthesis. There is a delicate balance between cytosolic MeCbl and mitochondrial AdoCbl synthesis, suggesting that the cblD protein is a branch point in intracellular cobalamin trafficking. Detailed data analysis indicated that the sequence after Met116 is sufficient for MeCbl synthesis, whereas the additional sequence between Met62 and Met116 is required for AdoCbl synthesis. The nature and location of mutations within the protein thus determines 1 of the 3 biochemical phenotypes, combined MMA/HC, isolated MMA, or isolated HC.
The Human Gene Nomenclature Committee designated this gene MMADHC (methylmalonic aciduria (cobalamin deficiency) cblD type, with homocystinuria).
In an Irish boy, born of consanguineous parents, with homocystinuria complementation group cblD (see 277410), Coelho et al. (2008) identified a homozygous 776C-T transition in the MMADHC gene, resulting in a leu259-to-pro (L259P) substitution. The mutation was not identified in 100 ethnically matched control chromosomes. The patient had been reported by Suormala et al. (2004) and had developmental delay, spastic ataxia, delayed visual evoked potentials, and increased mean corpuscular volume.
In an Italian boy with homocystinuria type cblD (see 277410), Coelho et al. (2008) identified compound heterozygosity for 2 mutations in the MMADHC gene: a 545C-A transversion resulting in a thr182-to-asn (T182N) substitution, and a 746A-G transition resulting in a tyr249-to-cys (Y249C; 611935.0003) substitution. Neither mutation was identified in 100 ethnically matched control chromosomes. He was diagnosed at age 3 months and showed hypotonia, nystagmus, dystonia, seizures, and megaloblastic anemia.
For discussion of the tyr249-to-cys (Y249C) mutation in the MMADHC gene that was found in compound heterozygous state in a patient with homocystinuria type cblD (see 277410) by Coelho et al. (2008), see 611935.0002.
In an Indian boy with methylmalonic aciduria complementation group cblD (see 277410), Coelho et al. (2008) identified a homozygous 8-bp deletion (57delCTCTTTAG) in the MMADHC gene, resulting in a frameshift and premature termination at codon 20. The patient was previously reported by Suormala et al. (2004). He was born prematurely at 32 weeks' gestation and showed severe respiratory distress syndrome, necrotizing enterocolitis, and seizures.
In a Haitian boy with methylmalonic aciduria type cblD (see 277410), Coelho et al. (2008) identified compound heterozygosity for 2 mutations in the MMADHC gene: a 160C-T transition resulting in an arg54-to-ter (R54X) substitution, and an 18-bp duplication (611935.0006) resulting in duplication of residues 103 to 108. He was diagnosed at age 11 months, and had severe ketotic coma, dehydration, hyperammonemia, leukopenia, and thrombocytopenia.
For discussion of the 18-bp duplication in the MMADHC gene that was found in compound heterozygous state in a patient with methylmalonic aciduria type cblD (see 277410) by Coelho et al. (2008), see 611935.0005.
In a Spanish American boy with combined methylmalonic aciduria and homocystinuria complementation group cblD (MAHCD; 277410) originally reported by Goodman et al. (1970), Coelho et al. (2008) identified a homozygous 748C-T transition in the MMADHC gene, resulting in an arg250-to-ter (R250X) substitution. The boy was born of consanguineous parents and had an acute psychotic episode, marfanoid appearance, nystagmus, mild mental retardation, and increased mean corpuscular volume.
In a Scandinavian girl with combined methylmalonic aciduria and homocystinuria complementation group cblD (MAHCD; 277410), Coelho et al. (2008) identified a homozygous 1-bp duplication (419dupA) in the MMADHC gene, resulting in a tyr140-to-ter (Y140X) substitution. She presented in early infancy with developmental delay, seizures, and megaloblastic anemia.
In an Italian boy with combined methylmalonic aciduria and homocystinuria complementation group cblD (MAHCD; 277410), born of consanguineous parents, Coelho et al. (2008) identified a homozygous 4-bp deletion (696+1delGTGA) in intron 7 of the MMADHC gene, resulting in the skipping of exon 7. The patient was diagnosed at age 22 days and showed poor feeding, encephalopathy, seizures, and increased mean corpuscular volume.
Coelho, D., Suormala, T., Stucki, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Newbold, R. F., Baumgartner, M. R., Fowler, B. Gene identification for the cblD defect of vitamin B12 metabolism. New Eng. J. Med. 358: 1454-1464, 2008. [PubMed: 18385497] [Full Text: https://doi.org/10.1056/NEJMoa072200]
Cooper, B. A., Rosenblatt, D. S., Watkins, D. Methylmalonic aciduria due to a new defect in adenosylcobalamin accumulation by cells. Am. J. Hemat. 34: 115-120, 1990. [PubMed: 2339678] [Full Text: https://doi.org/10.1002/ajh.2830340207]
Goodman, S. I., Moe, P. G., Hammond, K. B., Mudd, S. H., Uhlendorf, B. W. Homocystinuria with methylmalonic aciduria: two cases in a sibship. Biochem. Med. 4: 500-515, 1970. [PubMed: 5524089] [Full Text: https://doi.org/10.1016/0006-2944(70)90080-3]
Stucki, M., Coelho, D., Suormala, T., Burda, P., Fowler, B., Baumgartner, M. R. Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism. Hum. Molec. Genet. 21: 1410-1418, 2012. [PubMed: 22156578] [Full Text: https://doi.org/10.1093/hmg/ddr579]
Suormala, T., Baumgartner, M. R., Coelho, D., Zavadakova, P., Kozich, V., Koch, H. G., Berghauser, M., Wraith, J. E., Burlina, A., Sewell, A., Herwig, J., Fowler, B. The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis. J. Biol. Chem. 279: 42742-42749, 2004. [PubMed: 15292234] [Full Text: https://doi.org/10.1074/jbc.M407733200]