Combined enzymatic complex I and III deficiency associated with mutations in the nuclear encoded NDUFS4 gene

Biochem Biophys Res Commun. 2000 Aug 18;275(1):63-8. doi: 10.1006/bbrc.2000.3257.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Nucleus / genetics*
  • Cells, Cultured
  • Codon, Terminator / genetics
  • Consanguinity
  • DNA Mutational Analysis
  • DNA Primers
  • Electron Transport Complex I
  • Electron Transport Complex III / deficiency*
  • Electron Transport Complex III / genetics
  • Electron Transport Complex III / metabolism
  • Female
  • Fibroblasts
  • Genes, Lethal
  • Genotype
  • Humans
  • Infant
  • Leigh Disease / enzymology*
  • Leigh Disease / genetics*
  • Leigh Disease / pathology
  • Male
  • Mitochondria / enzymology*
  • Mitochondria / pathology
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / pathology
  • NADH, NADPH Oxidoreductases / deficiency*
  • NADH, NADPH Oxidoreductases / genetics
  • NADH, NADPH Oxidoreductases / metabolism
  • Oxidative Phosphorylation
  • Point Mutation / genetics
  • Polymorphism, Restriction Fragment Length


  • Codon, Terminator
  • DNA Primers
  • NADH, NADPH Oxidoreductases
  • Electron Transport Complex I
  • Electron Transport Complex III