Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
MMADHC encodes the cblD protein essential for intracellular processing of vitamin B₁₂ across mitochondrial and cytosolic pathways. Biallelic pathogenic variants in MMADHC cause methylmalonic aciduria and homocystinuria type cblD (MONDO:0010185). The disorder is inherited in an autosomal recessive manner and presents with isolated methylmalonic aciduria, isolated homocystinuria, or combined phenotypes. Clinical features span developmental delay, hematologic abnormalities such as anemia, neurologic dysfunction, and metabolic decompensation (PMID:18385497). Recognition of the cblD subtype guides specific metabolic management including cobalamin supplementation and targeted therapies. Accurate genetic diagnosis enables carrier detection and prenatal counseling.
The causal role of MMADHC was established by linkage mapping and functional complementation of patient fibroblasts in a cohort of seven unrelated individuals with cblD (PMID:18385497). Microcell-mediated chromosome transfer and refined genetic mapping localized MMADHC to chromosome 2q23.2. Transfection of wild-type MMADHC into cblD fibroblasts restored both adenosylcobalamin and methylcobalamin synthesis, confirming pathogenicity. This study identified diverse loss-of-function variants including splice-site, frameshift, and nonsense mutations. No significant genotype–phenotype correlation beyond biochemical subtype was noted at initial discovery. These findings provided definitive genetic validity for MMADHC in cblD.
Subsequent mechanistic studies have elucidated the dual-domain function of MMADHC in cobalamin partitioning. Expression vectors with mutations affecting mitochondrial leader sequences or introducing premature stop codons demonstrated that translation reinitiation and N-terminal context determine the balance between adenosylcobalamin and methylcobalamin synthesis (PMID:22156578). Mutant alleles such as c.653_654dup (p.Gly219fs) and c.746A>G (p.Tyr249Cys) exhibited domain-specific rescue profiles in patient-derived cell lines. These experiments support a single MMADHC protein with discrete cytosolic and mitochondrial targeting domains. Western blot analyses revealed truncated proteins corresponding to alternative initiation downstream of Met116. Collectively, these data clarify the molecular basis of the three biochemical phenotypes.
Proteomic and interaction assays confirmed that the C-terminal domain of MMADHC interacts with the upstream cobalamin chaperone CblC to regulate intracellular cofactor trafficking (PMID:23415655). Formation of CblC–CblD complexes was observed preferentially in the presence of dealkylated cobalamin species, underscoring an adapter-like function. Limited proteolysis defined a stable core spanning residues 116–296. Variants lacking the N-terminal 115 residues still retained CblC binding but failed to support full cobalamin assimilation. These findings reinforce a loss-of-function mechanism via disrupted protein–protein interactions. This mechanistic clarity aids interpretation of rare missense and truncating variants.
Recent translational readthrough studies have explored therapeutic avenues for MMADHC premature termination codons. Aminoglycoside-induced readthrough of variants such as c.646C>T (p.Arg216Ter) successfully restored full-length MMADHC expression in vitro (PMID:33552904). Readthrough efficiency was allele-specific and correlated with reestablished subcellular localization and cobalamin enzymatic activity. These results highlight the potential of pharmacological interventions to complement traditional cobalamin supplementation. Future clinical trials are warranted to evaluate efficacy and safety in patients. This approach offers a precision medicine strategy for select cblD alleles.
Integration of genetic, biochemical, and functional data yields a robust association between MMADHC and methylmalonic aciduria and homocystinuria type cblD. The body of evidence meets ClinGen criteria for a Strong gene–disease association, underpinned by seven unrelated probands with LoF alleles and concordant rescue experiments. Genetic evidence is rated Moderate given the absence of extensive familial segregation data. Functional evidence achieves a Strong tier based on rescue of cobalamin synthesis and detailed mechanistic insights. Additional studies, including animal models or comprehensive population analyses, could further refine genotype–phenotype correlations. Key take-home: Biallelic MMADHC variants conclusively define cblD, enabling precise diagnosis and laying groundwork for targeted therapies.
Gene–Disease AssociationStrong7 unrelated probands with biallelic MMADHC variants and concordant functional rescue Genetic EvidenceModerate7 probands with diverse loss-of-function alleles; no extensive familial segregation Functional EvidenceStrongWild-type MMADHC transfection rescues cobalamin synthesis; detailed mechanistic and readthrough studies |