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Human Molecular Genetics, 2001, Vol. 10, No. 5 529-535
© 2001 Oxford University Press

A nonsense mutation in the NDUFS4 gene encoding the 18 kDa (AQDQ) subunit of complex I abolishes assembly and activity of the complex in a patient with Leigh-like syndrome

Vittoria Petruzzella1, Rosaria Vergari1, Irene Puzziferri1, Domenico Boffoli1, Eleonora Lamantea2, Massimo Zeviani2 and Sergio Papa1,+

1Department of Medical Biochemistry and Biology, University of Bari, Piazza G. Cesare, 70124 Bari, Italy and 2Division of Biochemistry and Genetics, National Neurological Institute ‘C. Besta’, 20133 Milan, Italy

Sequence analysis of mitochondrial and nuclear candidate genes of complex I in children with deficiency of this complex and exhibiting Leigh-like syndrome has revealed, in one of them, a novel mutation in the NDUFS4 gene encoding the 18 kDa subunit. Phosphorylation of this subunit by cAMP-dependent protein kinase has previously been found to activate the complex. The present mutation consists of a homozygous G->A transition at nucleotide position +44 of the coding sequence of the gene, resulting in the change of a tryptophan codon to a stop codon. Such mutation causes premature termination of the protein after only 14 amino acids of the putative mitochondrial targeting peptide. Fibroblast cultures from the patient exhibited severe reduction of the rotenone-sensitive NADH->UQ oxidoreductase activity of complex I, which was insensitive to cAMP stimulation. Two-dimensional electrophoresis showed the absence of detectable normally assembled complex I in the inner mitochondrial membrane. These findings show that the expression of the NDUFS4 gene is essential for the assembly of a functional complex I.

+ To whom correspondence should be addressed. Tel: +39 080 5478428; Fax: +39 080 5478429; Email: papabchm@cimedoc.uniba.it


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