Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut- methylmalonic aciduria: identification of seven novel mutations

Mol Genet Metab. 2007 Mar;90(3):284-90. doi: 10.1016/j.ymgme.2006.10.002. Epub 2006 Nov 20.

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.

MeSH terms

  • Adolescent
  • Amino Acid Metabolism, Inborn Errors / genetics*
  • Amino Acid Metabolism, Inborn Errors / metabolism*
  • Apoenzymes / genetics
  • Child, Preschool
  • DNA Mutational Analysis
  • Genotype
  • Humans
  • Infant
  • Infant, Newborn
  • Methylmalonic Acid / urine*
  • Methylmalonyl-CoA Mutase / deficiency*
  • Methylmalonyl-CoA Mutase / genetics*
  • Mutation*
  • Phenotype

Substances

  • Apoenzymes
  • Methylmalonic Acid
  • Methylmalonyl-CoA Mutase