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

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...

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Bibliographic Details
Published in:Human molecular genetics 2001-03, Vol.10 (5), p.529-535
Main Authors: PETRUZZELLA, Vittoria, VERGARI, Rosaria, PUZZIFERRI, Irene, BOFFOLI, Domenico, LAMANTEA, Eleonora, ZEVIANI, Massimo, PAPA, Sergio
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Base Sequence
Biological and medical sciences
Cells, Cultured
Codon, Nonsense
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
DNA, Complementary
Electron Transport Complex I
Electrophoresis, Gel, Two-Dimensional
Female
Humans
Infant, Newborn
Leigh Disease - genetics
Leigh-like syndrome
Medical sciences
Molecular Sequence Data
NADH Dehydrogenase
NADH, NADPH Oxidoreductases - chemistry
NADH, NADPH Oxidoreductases - genetics
NADH^1UQ oxidoreductase
NDUFS4 gene
Neurology
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Summary: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.
ISSN:0964-6906
1460-2083
1460-2083
DOI:10.1093/hmg/10.5.529