NDUFS4 mutations cause Leigh syndrome with predominant brainstem involvement.
Complex I deficiency is a frequent cause of Leigh syndrome. We describe a non-consanguineous Ashkenazi-Sephardic Jewish patient with Leigh syndrome due to complex I deficiency. The clinical and neuroradiological presentation showed predominant brainstem involvement. Blue native polyacrylamide gel electrophoresis analysis revealed an impaired assembly of complex I. The patient was found to be compound heterozygous of two mutations in the NDUFS4 gene: p.Asp119His (a novel mutation) and p.Lys154fs (recently described in an Ashkenazi Jewish family). These findings support the suggestion that the p.Lys154fs mutation in NDUFS4 should be evaluated in Ashkenazi Jewish patients presenting with early onset Leigh syndrome even before enzymatic studies. Our results further demonstrated that NDUFS4 presents a hotspot of mutations in the genetic apparatus of oxidative phosphorylation and the correct assembly of the subunit it encodes is essential for completion of the assembly of complex I.
Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel. leshinsky@wolfson.health.gov.il
E
E
Leshinsky-Silver
Anne-Sophie
AS
Lebre
Limor
L
Minai
Ann
A
Saada
Julie
J
Steffann
Sarit
S
Cohen
Agnes
A
Rötig
Arnold
A
Munnich
Dorit
D
Lev
Tally
T
Lerman-Sagie
D001483:Base Sequence; D015153:Blotting, Western; D001933:Brain Stem / Q000473:pathology*; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000235:genetics; D017809:Fatal Outcome; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008931:Mitochondria, Muscle / Q000201:enzymology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000235:genetics*; D010085:Oxidative Phosphorylation
D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C427643:NDUFS4 protein, human