Molecular Genetic Characterization of 151 Mut‐Type Methylmalonic Aciduria Patients and Identification of 41 Novel Mutations in MUT. Issue 8 (23rd May 2016)

• Record Type: Journal Article
• Authors: Forny, Patrick; Schnellmann, Anne‐Sophie; Buerer, Celine; Lutz, Seraina; Fowler, Brian; Froese, D. Sean; Baumgartner, Matthias R.
• Is Part Of: Human mutation. Volume 37:Issue 8(2016)
• Page Start: 745
• Page End: 754
• Publication Date: 2016-05-23
• Subjects: methylmalonyl‐CoA mutase -- MUT -- methylmalonic aciduria -- missense variants -- genotype–phenotype correlation -- patient cohort; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23013
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : Isolated methylmalonic aciduria is an autosomal recessive disorder of propionate metabolism which is most commonly caused by mutations in the methylmalonyl‐CoA mutase ( MUT ) gene. We investigated a cohort of 151 patients and found a total of 110 different mutations, of which 41 were novel.This large scale mutation characterization helps to better understand the landscape of MUT mutations and their relationship to dysfunction and disease. 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.