Alternative titles; symbols
HGNC Approved Gene Symbol: MMAA
Cytogenetic location: 4q31.21 Genomic coordinates (GRCh38) : 4:145,619,385-145,660,033 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q31.21 | Methylmalonic aciduria, vitamin B12-responsive, cblA type | 251100 | Autosomal recessive | 3 |
Adenosylcobalamin (AdoCbl) is a cobalamin (cbl; vitamin B12)-containing coenzyme necessary for methylmalonyl-CoA mutase (MUT; 609058) activity. The MMAA protein is involved in the translocation of cbl into mitochondria for the final steps of AdoCbl synthesis (Dobson et al., 2002).
Dobson et al. (2002) identified MMAA within a bacterial operon containing MCM and, using the bacterial sequence, identified ESTs and assembled a full-length human MMAA cDNA. The deduced 418-amino acid protein has a calculated molecular mass of 46.5 kD. It contains an N-terminal mitochondrial leader sequence cleavage site, Walker A and B ATP-binding motifs, a Mg(2+)-binding site, and a GTP-binding site. MMAA shares 78.8% sequence identity with mouse Mmaa. Northern blot analysis revealed near ubiquitous expression of transcripts of 1.4, 2.6, and 5.5 kb, with highest expression in liver and skeletal muscle. Liver predominantly expressed the 1.4-kb transcript, while skeletal muscle predominantly expressed the 5.5-kb transcript.
Dobson et al. (2002) determined that the MMAA gene contains 7 exons and spans about 17.1 kb. Exon 1 is untranslated.
By genomic sequence analysis, Dobson et al. (2002) mapped the MMAA gene to chromosome 4q31.1-q31.2.
Mutations in the MMAA gene are responsible for the cblA type of methylmalonic aciduria (251100), which is vitamin B12-responsive. Dobson et al. (2002) analyzed fibroblast cell lines from 5 cblA patients and identified 4 mutations in the MMAA gene.
Lerner-Ellis et al. (2004) studied genomic DNA from 37 cblA patients for deleterious mutations in the MMAA gene by DNA sequencing of exons and flanking sequences. They identified 18 novel mutations, bringing the total number of mutations identified in 37 cblA patients to 22. A total of 13 mutations resulted in premature stop codons; 3 are splice site defects; and 6 are missense mutations that occur at highly conserved residues. Of these mutations, 8 were common to 2 or more individuals. An arg145-to-ter mutation (607481.0005) represented 43% of pathogenic alleles, and a common haplotype was identified.
In a fibroblast cell line from a patient with methylmalonic aciduria of the cblA type (251100), Dobson et al. (2002) identified a homozygous 4-bp deletion (ACTG) at nucleotide 592 of the MMAA gene. The mutation resulted in a frameshift that introduced a premature stop codon. Dobson et al. (2002) also identified this mutation in heterozygous state in a second patient and in compound heterozygous state with an 8-bp insertion (607481.0002) in a third patient.
In a fibroblast cell line from a patient with methylmalonic aciduria of the cblA type (251100), Dobson et al. (2002) identified compound heterozygosity for an 8-bp insertion (ATAAACTT) at nucleotide 260 of the MMAA gene and a 4-bp deletion (ACTG) at nucleotide 592 of the MMAA gene (607481.0001). Both mutations would result in a severely truncated protein.
In a fibroblast cell line from a patient with methylmalonic aciduria of the cblA type (251100), Dobson et al. (2002) identified heterozygosity for a C-to-T transition at nucleotide 283 of the MMAA gene, resulting in a gln95-to-ter (Q95X) substitution.
In a fibroblast cell line from a patient with methylmalonic aciduria of the cblA type (251100), Dobson et al. (2002) identified homozygosity for an A-to-G transition at nucleotide 620 of the MMAA gene, resulting in a tyr207-to-cys (Y207C) substitution.
In the genomic DNA of 37 cblA patients, Lerner-Ellis et al. (2004) identified 18 novel mutations in the MMAA gene, including a 433C-T transition (arg145 to ter; R145X) in exon 2 that represented 43% of pathogenic alleles; a common haplotype was identified.
Dobson, C. M., Wai, T., Leclerc, D., Wilson, A., Wu, X., Dore, C., Hudson, T., Rosenblatt, D. S., Gravel, R. A. Identification of the gene responsible for the cblA complementation group of vitamin B(12)-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements. Proc. Nat. Acad. Sci. 99: 15554-15559, 2002. [PubMed: 12438653] [Full Text: https://doi.org/10.1073/pnas.242614799]
Lerner-Ellis, J. P., Dobson, C. M., Wai, T., Watkins, D., Tirone, J. C., Leclerc, D., Dore, C., Lepage, P., Gravel, R. A., Rosenblatt, D. S. Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism. Hum. Mutat. 24: 509-516, 2004. Note: Erratum: Hum. Mutat. 25: 317 only, 2005. [PubMed: 15523652] [Full Text: https://doi.org/10.1002/humu.20104]