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Molecular Genetic Characterization of 151 Mut ‐Type Methylmalonic Aciduria Patients and Identification of 41 Novel Mutations in MUT
Author(s) -
Forny Patrick,
Schnellmann AnneSophie,
Buerer Celine,
Lutz Seraina,
Fowler Brian,
Froese D. Sean,
Baumgartner Matthias R.
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23013
Subject(s) - missense mutation , methylmalonic aciduria , biology , methylmalonic acidemia , mutase , allele , genetics , microbiology and biotechnology , gene , mutation , methylmalonic acid , biochemistry , endocrinology , homocysteine
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.