Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome.
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.
Bénit
P
P
Unité de Recherche sur les Handicaps Génétiques de l'Enfant (INSERM U393) and Département de Génétique, Hôpital Necker-Enfants Malades, Paris Cedex 15, France.
Slama
A
A
Cartault
F
F
Giurgea
I
I
Chretien
D
D
Lebon
S
S
Marsac
C
C
Munnich
A
A
Rötig
A
A
Rustin
P
P
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*
D007506:Iron-Sulfur Proteins; D021122:Protein Subunits; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C472512:NDUFS3 protein, human