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

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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 asmut0 and 32 asmut (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 withmut0 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 themut subclass were almost exclusively caused by missense mutations, found disproportionately in the C-terminal cofactor binding domain. On the contrary, only half of themut0 mutations were of the missense type. Western blot analysis revealed reduced MUT protein for all 34 cell lines (27mut0, sevenmut) tested, suggesting protein instability as a major mechanism of deficiency inmut-type MMA. This large-scale evaluation helps to characterize the landscape ofMUTmutations and their relationship to dysfunction and disease.

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