title: Molecular Genetic Characterization of 151 Mut-Type Methylmalonic Aciduria Patients and Identification of 41 Novel Mutations in MUT.
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.
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, CH-8032, Switzerland.|radiz - Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Forny
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, CH-8032, Switzerland.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Schnellmann
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, CH-8032, Switzerland.
authors.forename: Celine
authors.initials: C
authors.lastname: Buerer
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, CH-8032, Switzerland.
authors.forename: Seraina
authors.initials: S
authors.lastname: Lutz
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, CH-8032, Switzerland.
authors.forename: Brian
authors.initials: B
authors.lastname: Fowler
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, CH-8032, Switzerland.|radiz - Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Zurich, Switzerland.
authors.forename: D Sean
authors.initials: DS
authors.lastname: Froese
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, CH-8032, Switzerland.|radiz - Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
mesh_terms: D017668:Age of Onset; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D054643:INDEL Mutation; D008765:Methylmalonyl-CoA Mutase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D055550:Protein Stability
chemical_list: D008765:Methylmalonyl-CoA Mutase
keywords: MUT; genotype-phenotype correlation; methylmalonic aciduria; methylmalonyl-CoA mutase; missense variants; patient cohort