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.

TitleA 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.
Publication TypeJournal Article
Year of Publication2001
AuthorsPetruzzella, V, Vergari, R, Puzziferri, I, Boffoli, D, Lamantea, E, Zeviani, M, Papa, S
JournalHum Mol Genet
Volume10
Issue5
Pagination529-35
Date Published2001 Mar 01
ISSN0964-6906
KeywordsAmino Acid Sequence, Base Sequence, Cells, Cultured, Codon, Nonsense, DNA, Complementary, Electron Transport Complex I, Electrophoresis, Gel, Two-Dimensional, Female, Humans, Infant, Newborn, Leigh Disease, Molecular Sequence Data, NADH Dehydrogenase, NADH, NADPH Oxidoreductases
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 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.

DOI10.1093/hmg/10.5.529
Alternate JournalHum. Mol. Genet.
Citation Key10.1093/hmg/10.5.529
PubMed ID11181577