Alternative titles; symbols
HGNC Approved Gene Symbol: MMAB
Cytogenetic location: 12q24.11 Genomic coordinates (GRCh38) : 12:109,553,715-109,573,504 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.11 | Methylmalonic aciduria, vitamin B12-responsive, cblB type | 251110 | Autosomal recessive | 3 |
The MMAB gene encodes cob(I)alamin adenosyltransferase (EC 2.5.1.17), which catalyzes the final step in the synthesis of the cofactor adenosylcobalamin (AdoCbl). AdoCbl is a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase (MUT; 609058) (summary by Jorge-Finnigan et al., 2010).
Dobson et al. (2002) identified MMAB within a bacterial operon containing MCM and, using the bacterial sequence, identified ESTs and assembled a full-length human MMAB cDNA. The deduced 250-amino acid protein has a calculated molecular mass of 27.3 kD. MMAB shares 88% sequence identity with mouse Mmu. Northern blot analysis revealed expression of a 1.1-kb transcript, with highest expression in liver and skeletal muscle.
MMAB has 45% similarity to PduO, a cob(I)alamin adenosyltransferase, in Salmonella enterica (Johnson et al., 2001). Dobson et al. (2002) demonstrated that fibroblasts from 6 MMA patients from the cblB complementation group had levels of adenosyl-Cbl that were more than 13% that of control cells, as measured by uptake of radioactive OH-Cbl. Missense mutations in conserved amino acid residues of MMAB, as well as splice mutations in the gene among cblB group patients, added further evidence that the MMAB gene product functions as a cobalamin adenosyltransferase.
Forny et al. (2022) demonstrated that release of adenosylcobalamin from MMAB was activated by ATP and was favored in the presence of the MMUT protein. The authors also showed that adenosylcobalamin was not identified free in solution after release from MMAB, but instead bound to MMUT, suggesting a direct transfer.
Dobson et al. (2002) determined that the MMAB gene consists of 9 exons extending over 18.87 kb. Exon 9 ends at 2 alternative polyadenylation sites, and the intron-exon junctions are conserved between man and mouse. MMAB has a predicted leader sequence and signal cleavage site consistent with localization to the mitochondria.
By linkage analysis, Dobson et al. (2002) mapped the MMAB gene to chromosome 12q24.
Dobson et al. (2002) analyzed fibroblast cell lines from 6 patients with methylmalonic aciduria of the complementation type cblB patients and identified 6 mutations in the MMAB gene.
In 4 patients, including 2 sibs, with MMA type cblB, Jorge-Finnigan et al. (2010) identified 5 different mutations in the MMAB gene (607568.0004-607568.0008). Two of the mutations were missense and demonstrated in vitro to have decreased stability and decreased enzymatic activity compared to wildtype; the 3 other mutations were demonstrated to cause splice site defects in patient cells.
In 2 sibs with MMA type cblB, Brasil et al. (2015) identified compound heterozygous mutations in the MMAB gene (607568.0009-607568.0010). The patients were asymptomatic and identified through newborn screening.
In an Icelandic infant who died with severe heart failure and MMA type cblB, Agnarsdottir et al. (2022) identified homozygosity for the Icelandic founder mutation R191W (607568.0006).
Forny et al. (2022) identified 33 individual mutations in the MMAB gene in 97 patients with MMA type cblB, including 16 novel mutations. Missense mutations were the most common mutation type, and the most frequent missense mutations were R186W (607568.0001), identified in 57 alleles, and R191W (607568.0006), identified in 19 alleles. Q234X was the most common truncating mutation, identified in 14 alleles. Most of the mutations affected the C-terminal half of the protein, with a hotspot in exon 7. This hotspot, corresponding to residues 173-195, contributes to the binding sites of cobalamin and ATP. Functional studies were performed in fibroblasts from 76 patients and responsiveness to cobalamin, as measured by a propionate incorporation assay, was identified in association with the Q234X mutation. The R286W and R191W mutations showed no clear cobalamin response.
Among 6 MMA patients with methylmalonic aciduria of the cblB type (251110), Dobson et al. (2002) determined that 2 were homozygous for a 556C-T transition in the MMAB gene, which was predicted to result in an arg186-to-trp (R186W) substitution. In vitro uptake assays determined the adenosyl-Cbl levels in fibroblasts of these patients to be more than 4% of control cells. Three other patients were compound heterozygotes who each carried 1 of these mutant alleles. The allele frequency among 120 control cell lines was 1 of 60.
Dobson et al. (2002) described a Caucasian infant with methylmalonic aciduria of the cblB type (251110) who was a compound heterozygote for the R186W mutation (607568.0001) as well as a transition in the splice acceptor site of exon 3 of MMAB (IVS3 G-1A). An vitro uptake assay determined the adenosyl-Cbl level in fibroblasts of this patient to be more than 13% of control cells. The splice mutation was not found among 194 control alleles.
Dobson et al. (2002) described a Caucasian infant with methylmalonic aciduria of the cblB type (251110) who was a compound heterozygote for the R186W mutation (607568.0001) as well as a 5-bp deletion in exon 2. The mutation disrupts the reading frame after arg-190, leading to a premature termination codon. An vitro uptake assay determined the adenosyl-Cbl level in fibroblasts of this patient to be less than 1% of control cells.
In 3 patients, including 2 sibs, with methylmalonic aciduria of the cblB type (251110), Jorge-Finnigan et al. (2010) identified compound heterozygous mutations in the MMAB gene: all 3 patients carried a heterozygous c.287T-C transition (c.287T-C, NM_052845.3), resulting in an ile96-to-thr (I96T) substitution, on 1 allele. On the other allele, the 2 sibs carried a c.584G-A transition (607568.0005) affecting the last nucleotide of exon 7. Analysis of patient fibroblasts and minigene constructs showed that the c.584G-A mutation resulted in the skipping of exon 7 and premature termination (Ser174fs), although a smaller amount of the correctly spliced transcript (R195H) was observed. One sib had onset at age 4 years and died at age 4 years, whereas the other was diagnosed at age 3 months and was asymptomatic at age 5 years. The third patient carried a heterozygous c.571C-T transition on the other allele, resulting in an arg191-to-trp (R191W; 607568.0006) substitution. In vitro functional expression studies in E. coli showed that the I96T mutant protein had a decreased half-life and reduced protein expression compared to wildtype, as well as reduced enzymatic activity (about 60-65% compared to wildtype), but no significant differences in kinetic parameters. The R191W mutant protein was also highly unstable and showed reduced protein expression, as well as decreased enzymatic activity (about 52% of wildtype). Jorge-Finnigan et al. (2010) suggested that the I96T and R191W mutations may result in abnormal protein folding. By flow cytometry, Brasil et al. (2015) found increased levels of reactive oxygen species (ROS) in cells derived from the sibs reported by Jorge-Finnigan et al. (2010), with higher levels in the sib who died compared to the living sib. Patient fibroblasts also showed decreased oxygen consumption rate and mitochondrial abnormalities, including marked fission, reduced numbers of mitochondria, smaller mitochondria, lack of cristae, rarefaction of the matrix, and grain-like inclusions.
For discussion of the c.584G-A transition (c.584G-A, NM_052845.3) in the MMAB gene, resulting in a splice site alteration, skipping of exon 7, and premature termination (Ser174fs), that was found in compound heterozygous state in 2 sibs with methylmalonic aciduria of the cblB type (251110) by Jorge-Finnigan et al. (2010), see 607568.0004.
For discussion of the c.571C-T transition (c.571C-T, NM_052845.3) in the MMAB gene, resulting in an arg191-to-trp (R191W) substitution, that was found in compound heterozygous state in a patient with methylmalonic aciduria of the cblB type (251110) by Jorge-Finnigan et al. (2010), see 607568.0004.
In an Icelandic infant who died with severe dilated cardiomyopathy and MMA type cblB, Agnarsdottir et al. (2022) identified homozygosity for the R191W mutation, which they stated is an Icelandic founder mutation with a frequency of 1 in 270 Icelanders. The proband's unaffected parents were heterozygous for the mutation.
In a patient (P4) with methylmalonic aciduria of the cblB type (251110), Jorge-Finnigan et al. (2010) identified compound heterozygous mutations in the MMAB gene: a G-to-C transversion (c.349-1G-C, NM_052845.3) in intron 4, resulting in a splice site mutation and in-frame deletion of the first 6 nucleotides of exon 5 (Ile117_Gln118del), and a c.290G-A transition (607568.0008) in the last nucleotide of exon 3, resulting in the skipping of exon 3 (Gly66fs). The splicing defects were confirmed in patient fibroblasts and minigene assays. The patient had neonatal onset of the disorder, but was asymptomatic at age 12 years.
For discussion of the c.290G-A transition (c.290G-A, NM_052845.3) at the last nucleotide of exon 3 of the MMAB gene, resulting in the skipping of exon 3 (Gly66fs), that was found in compound heterozygous state in a patient with methylmalonic aciduria of the cblB type (251110), by Jorge-Finnigan et al. (2010), see 607568.0007.
In 2 asymptomatic sibs with methylmalonic aciduria of the cblB type (251110), Brasil et al. (2015) identified compound heterozygous mutations in exon 7 of the MMAB gene: a c.548A-T transversion (c.548A-T, NM_052845.3), resulting in a his183-to-leu (H183L) substitution, and a 3-bp in-frame duplication (c.568_570dup; 607568.0010), resulting in the duplication of residue arg190. Each unaffected parent was heterozygous for 1 of the mutations, which were not found in the Exome Variant Server database. In vitro functional expression studies in E. coli extracts showed that the H183L mutant had a decreased half-life (about 50% of wildtype) and an overall 75-fold reduction in ATP:cob(I)alamin adenosyltransferase (ATR) activity compared to wildtype, although kinetic data were similar to wildtype. The arg190dup mutant protein was highly unstable and could not be examined under any conditions. Flow cytometry showed increased levels of reactive oxygen species (ROXS) in patient cells, with higher levels in 1 sib compared to the other. Patient fibroblasts also showed decreased oxygen consumption rate and mitochondrial abnormalities, including marked fission, reduced numbers of mitochondria, decreased mitochondrial size, lack of cristae, rarefaction of the matrix, and grain-like inclusions. The patients were detected by newborn screening.
For discussion of the 3-bp in-frame duplication (c.568_570dup, NM_052845.3) in the MMAB gene, resulting in the duplication of residue arg190, that was found in compound heterozygous state in 2 sibs with methylmalonic aciduria of the cblB type (251110) by Brasil et al. (2015), see 607568.0009.
Agnarsdottir, D., Sigurjonsdottir, V. K., Emilsdottir, A. R., Petersen, E., Sigfusson, G., Rognvaldsson, I., Franzson, L., Vernon, H., Bjornsson, H. T. Early cardiomyopathy without severe metabolic dysregulation in a patient with cblB-type methylmalonic acidemia. Molec. Genet. Genomic Med. 10: e1971, 2022. [PubMed: 35712814] [Full Text: https://doi.org/10.1002/mgg3.1971]
Brasil, S., Richard, E., Jorge-Finnigan, A., Leal, F., Merinero, B., Banerjee, R., Desviat, L. R., Ugarte, M., Perez, B. Methylmalonic aciduria cblB type: characterization of two novel mutations and mitochondrial dysfunction studies. Clin. Genet. 87: 576-581, 2015. [PubMed: 24813872] [Full Text: https://doi.org/10.1111/cge.12426]
Dobson, C. M., Wai, T., Leclerc, D., Kadir, H., Narang, M., Lerner-Ellis, J. P., Hudson, T. J., Rosenblatt, D. S., Gravel, R. A. Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria. Hum. Molec. Genet. 11: 3361-3369, 2002. [PubMed: 12471062] [Full Text: https://doi.org/10.1093/hmg/11.26.3361]
Forny, P., Plessl, T., Frei, C., Burer, C., Froese, D. S., Baumgartner, M. R. Spectrum and characterization of bi-allelic variants in MMAB causing cblB-type methylmalonic aciduria. Hum. Genet. 141: 1253-1267, 2022. [PubMed: 34796408] [Full Text: https://doi.org/10.1007/s00439-021-02398-6]
Johnson, C. L. V., Pechonick, E., Park, S. D., Havemann, G. D., Leal, N. A., Bobik, T. A. Functional genomic, biochemical, and genetic characterization of the Salmonella pduO gene, an ATP:cob(I)alamin adenosyltransferase gene. J. Bacteriol. 183: 1577-1584, 2001. [PubMed: 11160088] [Full Text: https://doi.org/10.1128/JB.183.5.1577-1584.2001]
Jorge-Finnigan, A., Aguado, C., Sanchez-Alcudia, R., Abia, D., Richard, E., Merinero, B., Gamez, A., Banerjee, R., Desviat, L. R., Ugarte, M., Perez, B. Functional and structural analysis of five mutations identified in methylmalonic aciduria cblB type. Hum. Mutat. 31: 1033-1042, 2010. [PubMed: 20556797] [Full Text: https://doi.org/10.1002/humu.21307]