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 Petruzzella, Rosaria Vergari, Irene Puzziferri, Domenico Boffoli, Eleonora Lamantea, Massimo Zeviani, Sergio Papa

Research output: Contribution to journalArticlepeer-review

Abstract

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 activated 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 exhibiting 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.

Original languageEnglish
Pages (from-to)529-535
Number of pages7
JournalHuman Molecular Genetics
Volume10
Issue number5
Publication statusPublished - Mar 1 2001

ASJC Scopus subject areas

  • Genetics

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