J Med Genet 41:14-17 doi:10.1136/jmg.2003.014316
  • Short report

Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome

  1. P Bénit1,
  2. A Slama2,
  3. F Cartault3,
  4. I Giurgea1,
  5. D Chretien1,
  6. S Lebon1,
  7. C Marsac4,
  8. A Munnich1,
  9. A Rötig1,
  10. P Rustin1
  1. 1Unité de Recherche sur les Handicaps Génétiques de l’Enfant (INSERM U393) and Département de Génétique, Hôpital Necker-Enfants Malades, Paris Cedex 15, France
  2. 2Laboratoire de Biochimie 1, AP-HP Hôpital de Bicêtre, Le Kremlin Bicêtre Cedex, France
  3. 3Centre Hospitalier Départemental Félix Guyon, Service Génétique Bellepierre, Saint-Denis Cedex, La Réunion, France
  4. 4CERTO Faculté Necker-Enfants Malades, Paris Cedex 15
  1. Correspondence to:
 Dr Pierre Rustin
 INSERM U393, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France; rustin
  • Received 9 September 2003
  • Accepted 15 October 2003


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.