title: Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome.
abstract: Respiratory chain complex I deficiency represents a genetically heterogeneous group of diseases resulting from mutations in mitochondrial or nuclear genes. Mutations have been reported in 13 of the 14 subunits encoding the core of complex I (seven mitochondrial and six nuclear genes) and these result in Leigh or Leigh-like syndromes or cardiomyopathy. In this study, a combination of denaturing high performance liquid chromatography and sequence analysis was used to study the NDUFS3 gene in a series of complex I deficient patients. Mutations found in this gene (NADH dehydrogenase iron-sulphur protein 3), coding for the seventh and last subunit of complex I core, were shown to cause late onset Leigh syndrome, optic atrophy, and complex I deficiency. A biochemical diagnosis of complex I deficiency on cultured amniocytes from a later pregnancy was confirmed through the identification of disease causing NDUFS3 mutations in these cells. While mutations in the NDUFS3 gene thus result in Leigh syndrome, a dissimilar clinical phenotype is observed in mutations in the NDUFV2 and NDUFS2 genes, resulting in encephalomyopathy and cardiomyopathy. The reasons for these differences are uncertain.
authors.affiliation: Unité de Recherche sur les Handicaps Génétiques de l'Enfant (INSERM U393) and Département de Génétique, Hôpital Necker-Enfants Malades, Paris Cedex 15, France.
authors.forename: P
authors.initials: P
authors.lastname: Bénit
authors.forename: A
authors.initials: A
authors.lastname: Slama
authors.forename: F
authors.initials: F
authors.lastname: Cartault
authors.forename: I
authors.initials: I
authors.lastname: Giurgea
authors.forename: D
authors.initials: D
authors.lastname: Chretien
authors.forename: S
authors.initials: S
authors.lastname: Lebon
authors.forename: C
authors.initials: C
authors.lastname: Marsac
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: A
authors.initials: A
authors.lastname: Rötig
authors.forename: P
authors.initials: P
authors.lastname: Rustin
mesh_terms: D002648:Child; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics*; D017809:Fatal Outcome; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000172:deficiency / Q000235:genetics; D007888:Leigh Disease / Q000201:enzymology / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000172:deficiency / Q000235:genetics*; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics*
chemical_list: D007506:Iron-Sulfur Proteins; D021122:Protein Subunits; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C472512:NDUFS3 protein, human