Molecular Genetic Characterization of 151Mut-Type Methylmalonic Aciduria Patients and Identification of 41 Novel Mutations inMUT

Abstract

Isolated methylmalonic aciduria (MMA) is an autosomal-recessive disorder of propionate metabolism that is most commonly caused by mutations in the methylmalonyl-CoA mutase (MUT) gene (mut-type MMA). We investigated a cohort of 151 patients, classifying 114 patients as mut(0) and 32 as mut(-) (five not defined). As per the definition, mut(-) patients showed a higher propionate incorporation ratio in vitro, which was correlated to a considerably later age of onset compared with mut(0) patients. In all patients, we found a total of 110 different mutations, of which 41 were novel. While the missense alleles p.Asn219Tyr, p.Arg369His, and p.Arg694Trp recurred in >10 alleles, 47 mutations were identified only once, suggesting many patients carry private mutations. Deficient alleles in the mut(-) subclass were almost exclusively caused by missense mutations, found disproportionately in the C-terminal cofactor binding domain. On the contrary, only half of the mut(0) mutations were of the missense type. Western blot analysis revealed reduced MUT protein for all 34 cell lines (27 mut(0) , seven mut(-) ) tested, suggesting protein instability as a major mechanism of deficiency in mut-type MMA. This large-scale evaluation helps to characterize the landscape of MUT mutations and their relationship to dysfunction and disease.

Liver neoplasms in methylmalonic aciduria: An emerging complication

“…All mutations of cases 1 to 4 were previously associated with a severe phenotype, except for the novel MMAB mutation c.643A>G p.(Arg215Gly) in case 1. Case 2 was homozygous for a truncating mutation resulting in p.(Tyr231*), yielding no functional enzyme . The common severe catalytic mutant p.(Asn219Tyr) was found in cases 3 and 4.…”

“…Case 2 was homozygous for a truncating mutation resulting in p.(Tyr231*), yielding no functional enzyme. 1 The common severe catalytic mutant p.(Asn219Tyr) 7 was found in cases 3 and 4. Case 3 also harbored the p.(Ala137Val) mutant, a mut 0 allele in exon 3, which corresponds in a large part to the essential substrate-binding site of MMUT, 8 whereas case 4 carried the severe catalytic and folding mutant p.…”

“…Isolated methylmalonic aciduria (MMA) is an autosomal recessive disorder of propionate metabolism caused by mutations in the MMUT gene ( mut subtype, OMIM: 251000) encoding methylmalonyl‐CoA mutase (MMUT, EC 5.4.99.2), which requires adenosylcobalamin as a cofactor. Failure to produce and deliver the cofactor to its target enzyme MMUT also results in MMA, involving mutations in the MMAA ( cblA subtype, OMIM: 251100) and MMAB ( cblB subtype, OMIM: 251110) genes.…”

Protein destabilization and loss of protein‐protein interaction are fundamental mechanisms in cblA ‐type methylmalonic aciduria

“…On the other hand, missense mutations occurred only at a frequency of 16%. This is in contrast to other metabolic diseases (Caldovic, Abdikarim, Narain, Tuchman, & Morizono, ; Mitchell, Trakadis, & Scriver, ) and to other proteins in the vitamin B 12 pathway (Forny et al., ), where missense mutations represent the majority of identified mutations. We found it of particular interest to determine the mechanism by which single amino acid changes in MMAA lead to malfunction and disease.…”

Long‐term outcome of methylmalonic aciduria after kidney, liver, or combined liver‐kidney transplantation: The French experience

“…MMA was measured in the plasma and urine by gas chromatography‐mass spectrometry. MUT (Methylmalonyl‐CoA mutase, GenBank: NG_007100), MMAA (Methylmalonic Acidemia type A, cblA, GenBank: NG_007536) and MMAB (Methylmalonic Acidemia type B, cblB, GenBank: NG_007096) genes were sequenced …”