RESUMO
Methylmalonic aciduria (MMA) is an autosomal recessive inborn error of metabolism that results from functional defects in methylmalonyl CoA mutase (MCM), a nuclear-encoded, mitochondrial enzyme that uses the vitamin B12 derivative, adenosylcobalamin (AdoCbl) as a cofactor. To date, 23 mutations have been identified at the MUT locus on the short arm of chromosome 6, causing the mut forms of MMA (mut complementation group; mut MMA, McKusick #251000). We now report seven novel mutations. Three were found inmut0 patients: R228Q (c759G-->A) was found as a heterozygous change; G312V (c1011G-->T) and 346delL (c1112delCTT) were both found as homozygous changes. Four mutations were found in mut patients: A191E (c648C-->A) and V633G (c1974T-->G) were found in the same patient; 684insL (c2128insCTC) and L685R (c2130T-->G) were both found as homozygous changes. The recent modelling of the human methylmalonyl CoA mutase allowed for an interpretation of the identified mutations.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Ácido Metilmalônico/urina , Mutação , Alelos , Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Erros Inatos do Metabolismo dos Aminoácidos/urina , Sequência de Bases , Linhagem Celular , Cromossomos Humanos Par 6/genética , DNA/genética , Primers do DNA/genética , Teste de Complementação Genética , Humanos , Metilmalonil-CoA Mutase/deficiência , Metilmalonil-CoA Mutase/genética , Reação em Cadeia da PolimeraseAssuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , População Negra/genética , Ácido Metilmalônico/urina , Metilmalonil-CoA Mutase/genética , Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Substituição de Aminoácidos , Células Cultivadas , DNA/química , DNA/genética , Análise Mutacional de DNA , Homozigoto , Humanos , Masculino , Mutação , Mutação PuntualRESUMO
Methionine synthase catalyzes the remethylation of homocysteine to methionine in a methylcobalamin-dependent reaction. We used specific regions of homology within the methionine synthase sequences of several lower organisms to clone a human methionine synthase cDNA by a combination of RT-PCR and inverse PCR. The enzyme is 1265 amino acids in length and contains the seven residue structure-based sequence fingerprint identified for cobalamin-containing enzymes. The gene was localized to chromosome 1q43 by the FISH technique. We have identified one missense mutation and a 3 bp deletion in patients of the cblG complementation group of inherited homocysteine/folate disorders by SSCP and sequence analysis, as well as an amino acid substitution present in high frequency in the general population. We discuss the possibility that a mild deficiency of methionine synthase activity could be associated with mild hyperhomocysteinemia, a risk factor for cardiovascular disease and possibly neural tube defects.
