title: N219Y, a new frequent mutation among mut(degree) forms of methylmalonic acidemia in Caucasian patients.
abstract: Mutations in the MUT locus encoding for the methylmalonyl-CoA mutase (MCM) apoenzyme are responsible for the mut forms of methylmalonic acidemia (MMA). To date, 49 different mutations have been identified in mut MMA. Only two frequent mutations have been reported in the Japanese population and in African-Americans. Here we report a new missense mutation N219Y (731 A-->T) which we found in five unrelated families of French and Turkish descent. All the patients exhibited a severe mut(degree) phenotype and three of them were homozygotes for N219Y. Direct involvement of the mutation in the loss of enzyme activity was demonstrated by mutagenesis and transient expression study. Mapping of the mutation onto a three-dimensional model of human MCM constructed by homology with the Propionibacterium shermanii enzyme shows that it lies in a highly conserved secondary structure motif and might suggest impaired folding and/or poor stability compatible with the mut(degree) phenotype. Finally, a 1% N219Y carrier frequency was observed in a French anonymous control population. Thus, N219Y is the first frequent mut mutation to be reported in the Caucasian population.
authors.affiliation: Service de Biochimie-Génétique/INSERM U458, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Acquaviva
authors.forename: J F
authors.initials: JF
authors.lastname: Benoist
authors.forename: I
authors.initials: I
authors.lastname: Callebaut
authors.forename: N
authors.initials: N
authors.lastname: Guffon
authors.forename: H
authors.initials: H
authors.lastname: Ogier de Baulny
authors.forename: G
authors.initials: G
authors.lastname: Touati
authors.forename: A
authors.initials: A
authors.lastname: Aydin
authors.forename: D
authors.initials: D
authors.lastname: Porquet
authors.forename: J
authors.initials: J
authors.lastname: Elion
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D001216:Asparagine / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008764:Methylmalonic Acid / Q000097:blood* / Q000378:metabolism; D008765:Methylmalonyl-CoA Mutase / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D014443:Tyrosine / Q000235:genetics; D044465:White People / Q000235:genetics*
chemical_list: D014443:Tyrosine; D001216:Asparagine; D008764:Methylmalonic Acid; D008765:Methylmalonyl-CoA Mutase