title: Molecular studies in mutase-deficient (MUT) methylmalonic aciduria: identification of five novel mutations.
abstract: Mutase-deficient (MUT) methylmalonic aciduria (MMA) is an autosomal recessive inborn error of organic acid metabolism, resulting from a functional defect in the nuclear encoded mitochondrial enzyme methylmalonyl-CoA mutase (MCM) (EC.5.4.99.2). The enzyme requires 5'-deoxyadenosylcobalamin as a cofactor. Isolated MMA results from either apoenzyme or cofactor defects, and is classified into several genotypic classes and complementation groups. These are designated mut(-) or mut(0) (together termed mut), depending on minimal or no apoenzyme activity respectively and cobalamin A or B (cbl A/B) for cofactor defects. To date various studies have identified over 53 disease-causing mutations from patients with mut(0/-) MMA. These are predominantly missense/nonsense nucleotide substitutions. In this study, we report the genotype analysis on 7 patients diagnosed with mut MMA. Five novel mutations were identified (R403stop, 497delG, P615T, 208delG and R467stop) and one novel polymorphism (c712A->G). The previously reported R228Q mutation was found in one patient, who is a compound heterozygote for this mutation and the R467stop mutation. A recently reported N219Y mutation was found in one patient. The 497delG mutation was detected as a homozygous deletion. The remaining mutations were observed in compound heterozygotes, with the second mutation yet to be identified. Many of the unidentified mutations may occur within the promotor or intronic regions.
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia. petersh@cryptic.rch.unimelb.edu.au
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Peters
authors.forename: Mikhael
authors.initials: M
authors.lastname: Nefedov
authors.forename: Lai Wah
authors.initials: LW
authors.lastname: Lee
authors.forename: Jose E
authors.initials: JE
authors.lastname: Abdenur
authors.forename: Nestor A
authors.initials: NA
authors.lastname: Chamoles
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kahler
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Ioannou
mesh_terms: D005838:Genotype; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008764:Methylmalonic Acid / Q000652:urine*; D008765:Methylmalonyl-CoA Mutase / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation; D011110:Polymorphism, Genetic
chemical_list: D008764:Methylmalonic Acid; D008765:Methylmalonyl-CoA Mutase