title: Combined enzymatic complex I and III deficiency associated with mutations in the nuclear encoded NDUFS4 gene.
abstract: Combined OXPHOS-system enzyme deficiencies are observed in approximately 25% of all OXPHOS-system disturbances. Of these, combined complex I and III deficiency is relatively scarce. So far, only mtDNA and thymidine phosphorylase (TP) mutations have been associated with combined OXPHOS-system disturbances. In this report we show, for the first time, that a nuclear gene mutation in a structural, nuclear encoded complex I gene is associated with combined complex I and III deficiency. After our initial report we describe mutations in the NDUFS4 gene of complex I in two additional patients. The first mutation is a deletion of G at position 289 or 290. Amino acid 96 changes from a tryptophan to a stop codon. The mutation was found homozygous in the patient; both parents are heterozygous for the mutation. The second mutation is a transition from C to T at cDNA position 316. Codon is changed from CGA (arginine) to TGA (stop). The patient is homozygous for the mutation; both parents are heterozygous. Both mutations in the NDUFS4 gene led to a premature stop in Leigh-like patients with an early lethal phenotype. We hypothesise that the structural integrity of the OXPHOS system, in mammal supermolecular structures, may be responsible for the observed biochemical features.
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders, University Medical Centre Nijmegen, Nijmegen, The Netherlands.
authors.forename: S M
authors.initials: SM
authors.lastname: Budde
authors.forename: L P
authors.initials: LP
authors.lastname: van den Heuvel
authors.forename: A J
authors.initials: AJ
authors.lastname: Janssen
authors.forename: R J
authors.initials: RJ
authors.lastname: Smeets
authors.forename: C A
authors.initials: CA
authors.lastname: Buskens
authors.forename: L
authors.initials: L
authors.lastname: DeMeirleir
authors.forename: R
authors.initials: R
authors.lastname: Van Coster
authors.forename: M
authors.initials: M
authors.lastname: Baethmann
authors.forename: T
authors.initials: T
authors.lastname: Voit
authors.forename: J M
authors.initials: JM
authors.lastname: Trijbels
authors.forename: J A
authors.initials: JA
authors.lastname: Smeitink
mesh_terms: D001483:Base Sequence; D002467:Cell Nucleus / Q000235:genetics*; D002478:Cells, Cultured; D018388:Codon, Terminator / Q000235:genetics; D003241:Consanguinity; D004252:DNA Mutational Analysis; D017931:DNA Primers; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts; D005804:Genes, Lethal; D005838:Genotype; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D017354:Point Mutation / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D018388:Codon, Terminator; D017931:DNA Primers; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III