RESUMO
Mitochondrial complex I deficiency is the most frequently encountered defect of the oxidative phosphorylation system. To identify the genetic cause of the complex I deficiency, we screened the gene encoding the NDUFS1 subunit. We report 3 patients with low residual complex I activity expressed in cultured fibroblasts, which displayed novel mutations in the NDUFS1 gene. One mutation introduces a premature stop codon, 3 mutations cause a substitution of amino acids and another mutation a deletion of one amino acid. The fibroblasts of the patients display a decreased amount and activity of complex I. In addition, a disturbed assembly pattern was observed. These results suggest that NDUFS1 is a prime candidate to screen for disease-causing mutations in patients with a very low residual complex I activity in cultured fibroblasts.
Assuntos
Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/genética , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Mutação , NADH Desidrogenase/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Sequência de Bases , Encéfalo/patologia , Células Cultivadas , Criança , Pré-Escolar , Códon sem Sentido , Análise Mutacional de DNA , Feminino , Fibroblastos/enzimologia , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Doenças Mitocondriais/patologia , Deleção de Sequência , Homologia de Sequência de AminoácidosRESUMO
Failure to thrive, feeding difficulties, variable forms of infantile epilepsy or psychomotor developmental delay and hypotonia were the most frequent clinical disease presentations in eight children with combined oxidative phosphorylation enzyme complex deficiencies carrying mutations in the polymerase gamma (POLG1) gene. Five out of eight patients developed severe liver dysfunction during the course of the disease. Three of these patients fulfilled the disease criteria for Alpers syndrome. Most children showed deficiencies of respiratory chain enzyme complexes I and III, in combination with complex II, complex IV and/or PDHc in muscle, whereas in fibroblasts normal enzyme activities were measured. All children carried homozygous or compound heterozygous mutations in the POLG1 gene, including two novel mutations in association with mtDNA depletion. Conclusion We suggest performing POLG1 mutation analysis in children with combined oxidative phosphorylation deficiencies in muscle, even if the clinical picture is not Alpers syndrome.