title: Molecular basis of methylmalonyl-CoA mutase apoenzyme defect in 40 European patients affected by mut(o) and mut- forms of methylmalonic acidemia: identification of 29 novel mutations in the MUT gene.
abstract: Methylmalonyl-CoA mutase (MCM) apoenzyme deficiency is a rare metabolic disease that may result in distinct biochemical phenotypes of methylmalonic acidemia (MMA), namely mut(o) and mut-. We analyzed a cohort of 40 MCM-deficient patients with MMA affected by either the mut(o) or the mut- form of the disease. By direct sequencing of cDNA and gDNA of the MUT gene, we detected 42 mutations, 29 of which were novel mutations. These included five frameshift mutations (insertion, deletion, or duplication of a single nucleotide), five sequence modifications in consensus splice sites, six nonsense and 12 missense mutations, and a large genomic deletion including exon 12. We explored how the 12 novel missense mutations might cause the observed phenotype by mapping them onto a three-dimensional model of the human MCM generated by homology with the P. shermanii enzyme. In this work we update the spectrum of MCM mutations (n=84), and then discuss their prevalence and distribution throughout the coding sequence in relation to the enzyme structure.
authors.affiliation: Fédération de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Acquaviva
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Benoist
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pereira
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.forename: Thu
authors.initials: T
authors.lastname: Koskas
authors.forename: Dominique
authors.initials: D
authors.lastname: Porquet
authors.forename: Jacques
authors.initials: J
authors.lastname: Elion
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000145:classification / Q000235:genetics; D001051:Apoenzymes / Q000235:genetics; D001483:Base Sequence; D002648:Child; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005060:Europe; D016368:Frameshift Mutation; D006801:Humans; D008764:Methylmalonic Acid / Q000652:urine*; D008765:Methylmalonyl-CoA Mutase / Q000172:deficiency* / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D022821:RNA Splice Sites; D017384:Sequence Deletion
chemical_list: D001051:Apoenzymes; D018389:Codon, Nonsense; D022821:RNA Splice Sites; D008764:Methylmalonic Acid; D008765:Methylmalonyl-CoA Mutase