title: A novel mutation of the NDUFS7 gene leads to activation of a cryptic exon and impaired assembly of mitochondrial complex I in a patient with Leigh syndrome.
abstract: Complex I deficiency is a frequent cause of mitochondrial disease as it accounts for one third of these disorders. By genotyping several putative disease loci using microsatellite markers we were able to describe a new NDUFS7 mutation in a consanguineous family with Leigh syndrome and isolated complex I deficiency. This mutation lies in the first intron of the NDUFS7 gene (c.17-1167 C>G) and creates a strong donor splice site resulting in the generation of a cryptic exon. This mutation is predicted to result in a shortened mutant protein of 41 instead of 213 amino acids containing only the first five amino acids of the normal protein. Analysis of the assembly state of the respiratory chain complexes under native condition revealed a marked decrease of fully assembled complex I while the quantity of the other complexes was not altered. These results report the first intronic NDUFS7 gene mutation and demonstrate the crucial role of NDUFS7 in the biogenesis of complex I.
authors.affiliation: Service de Génétique and INSERM U781, Hôpital Necker Enfants Malades, 149 rue de Sèvres, 75015 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lebon
authors.forename: Limor
authors.initials: L
authors.lastname: Minai
authors.forename: Dominique
authors.initials: D
authors.lastname: Chretien
authors.forename: Johanna
authors.initials: J
authors.lastname: Corcos
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.forename: Noman
authors.initials: N
authors.lastname: Kadhom
authors.forename: Julie
authors.initials: J
authors.lastname: Steffann
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Pauchard
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Bonnefont
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics; D007888:Leigh Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000235:genetics*; D010375:Pedigree; D012326:RNA Splicing
chemical_list: D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C496410:NDUFS7 protein, human