title: Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency.
abstract: Reduced nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) is the largest complex of the mitochondrial respiratory chain and complex I deficiency accounts for approximately 30% cases of respiratory-chain deficiency in humans. Only seven mitochondrial DNA genes, but >35 nuclear genes encode complex I subunits. In an attempt to elucidate the molecular bases of complex I deficiency, we studied the six most-conserved complex I nuclear genes (NDUFV1, NDUFS8, NDUFS7, NDUFS1, NDUFA8, and NDUFB6) in a series of 36 patients with isolated complex I deficiency by denaturing high-performance liquid chromatography and by direct sequencing of the corresponding cDNA from cultured skin fibroblasts. In 3/36 patients, we identified, for the first time, five point mutations (del222, D252G, M707V, R241W, and R557X) and one large-scale deletion in the NDUFS1 gene. In addition, we found six novel NDUFV1 mutations (Y204C, C206G, E214K, IVS 8+41, A432P, and del nt 989-990) in three other patients. The six unrelated patients presented with hypotonia, ataxia, psychomotor retardation, or Leigh syndrome. These results suggest that screening for complex I nuclear gene mutations is of particular interest in patients with complex I deficiency, even when normal respiratory-chain-enzyme activities in cultured fibroblasts are observed.
authors.affiliation: INSERM U393, Service de Génétique, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Bénit
authors.forename: D
authors.initials: D
authors.lastname: Chretien
authors.forename: N
authors.initials: N
authors.lastname: Kadhom
authors.forename: P
authors.initials: P
authors.lastname: de Lonlay-Debeney
authors.forename: V
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: A
authors.initials: A
authors.lastname: Cabral
authors.forename: S
authors.initials: S
authors.lastname: Peudenier
authors.forename: P
authors.initials: P
authors.lastname: Rustin
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: A
authors.initials: A
authors.lastname: Rötig
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000595:Amino Acid Sequence; D001483:Base Sequence; D020134:Catalytic Domain; D002467:Cell Nucleus / Q000235:genetics; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D004579:Electron Transport / Q000235:genetics; D042967:Electron Transport Complex I; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D005817:Genetic Counseling; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007888:Leigh Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008931:Mitochondria, Muscle / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D009245:NADH Dehydrogenase; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D009691:Nucleic Acid Denaturation; D017354:Point Mutation / Q000235:genetics*; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: C112232:NDUFV1 protein, human; D011506:Proteins; D009247:NADH, NADPH Oxidoreductases; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I