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Case Reports
. 2000 Aug 18;275(1):63-8.
doi: 10.1006/bbrc.2000.3257.

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

S M Budde  1 , L P van den Heuvel, A J Janssen, R J Smeets, C A Buskens, L DeMeirleir, R Van Coster, M Baethmann, T Voit, J M Trijbels, J A Smeitink
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Case Reports

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

S M Budde et al. Biochem Biophys Res Commun. .

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.

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