title: Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut- methylmalonic aciduria: identification of seven novel mutations.
abstract: Isolated methylmalonic acidurias (MMA-urias) comprise a group of rare autosomal recessively inherited disorders characterised by accumulation of MMA in urine and other body fluids, resulting from deficient activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MCM). Isolated MMA-uria results from either MCM apoenzyme defects (mut(0) and mut(-)) or defects in synthesis of its cofactor 5-deoxyadenosylcobalamin, i.e. cblA, cblB and cblD-variant 2. To date various studies have identified 171 disease-causing mutations in the MCM gene (MUT). We report mutation analysis in 32 probands with mut MMA-uria including 13 probands with a mut(-) defect. Sixty two of 64 possible mutant alleles were identified, seven of which were novel missense alleles. We found three novel mutations (c.427C>T/p.H143Y; c.862T>C/p.S288P; c.1361G>A/p.G454E) among 19 probands with a mut(0) defect and four novel mutations (c.299A>G/p.Y100C; c.1031C>T/p.S344F; c.1097A>G/p.N366S; c.2081G>T/p.R694L) among 13 probands with a mut(-) defect. Our study provides evidence that the p.Y100C, p.R108H, p.N366S, p.V633G, p.R694W, p.R694L and p.M700K mutations are associated with a mut(-) phenotype.
authors.affiliation: Division of Metabolism and Molecular Pediatrics, University Children's Hospital Zurich, Switzerland.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lempp
authors.forename: Terttu
authors.initials: T
authors.lastname: Suormala
authors.forename: Renate
authors.initials: R
authors.lastname: Siegenthaler
authors.forename: E Regula
authors.initials: ER
authors.lastname: Baumgartner
authors.forename: Brian
authors.initials: B
authors.lastname: Fowler
authors.forename: Beat
authors.initials: B
authors.lastname: Steinmann
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
mesh_terms: D000293:Adolescent; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism*; D001051:Apoenzymes / Q000235:genetics; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008764:Methylmalonic Acid / Q000652:urine*; D008765:Methylmalonyl-CoA Mutase / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation; D010641:Phenotype
chemical_list: D001051:Apoenzymes; D008764:Methylmalonic Acid; D008765:Methylmalonyl-CoA Mutase