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

Combined OXPHOS-system enzyme deficiencies are observed in approximately 25 % of all OXPHOS-system disturbances. Of these, combined complex I and III d eficiency is relatively scarce. So far,only mtDNA and thymidine phosphoryla se (TP) mutations have been associated with combined OXPHOS-system disturba nces. In this report me show, for the first time, that a nuclear gene mutat ion in a structural, nuclear encoded complex I gene is associated with comb ined complex I and III deficiency. After our initial report we describe mut ations in the NDUFS4 gene of complex I in two additional patients. The firs t mutation is a deletion of G: at position 289 or 290. Amino acid 96 change s from a tryptophan to a stop codon. The mutation was found homozygous in t he patient; both parents are heterozygous for the mutation. The second muta tion is a transition from C to T at cDNA position 316. Codon is changed fro m 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 hy pothesise that the structural integrity of the OXPHOS system, in mammal sup ermolecular structures, may be responsible for the observed biochemical fea tures. (C) 2000 Academic Press.