title: A novel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family.
abstract: Leigh syndrome is a neurodegenerative disorder of infancy or childhood generally due to mutations in nuclear or mitochondrial genes involved in mitochondrial energy metabolism. We performed linkage analysis in an Ashkenazi Jewish (AJ) family without consanguinity with three affected children. Linkage to microsatellite markers D5S1969 and D5S407 led to evaluation of the complex I gene NDUFS4, in which we identified a novel homozygous c.462delA mutation that disrupts the reading frame. The resulting protein lacks a cAMP-dependent protein kinase phosphorylation site required for activation of mitochondrial respiratory chain complex I. In a random sample of 5000 healthy AJ individuals, the carrier frequency of the NDUFS4 mutation c.462delA was 1 in 1000, suggesting that it should be considered in all AJ patients with Leigh syndrome.
authors.affiliation: Department of Biological Sciences, Fordham University, 441 E. Fordham Rd., Bronx, NY 10458, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Anderson
authors.forename: W K
authors.initials: WK
authors.lastname: Chung
authors.forename: J
authors.initials: J
authors.lastname: Frezzo
authors.forename: J C
authors.initials: JC
authors.lastname: Papp
authors.forename: J
authors.initials: J
authors.lastname: Ekstein
authors.forename: S
authors.initials: S
authors.lastname: DiMauro
authors.forename: B Y
authors.initials: BY
authors.lastname: Rubin
mesh_terms: D000328:Adult; D001483:Base Sequence; D002675:Child, Preschool; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000378:metabolism; D017809:Fatal Outcome; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D040941:Heredity; D006720:Homozygote; D006801:Humans; D007223:Infant; D007585:Jews / Q000235:genetics*; D007888:Leigh Disease / Q000150:complications / Q000175:diagnosis / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D010766:Phosphorylation; D011247:Pregnancy; D011499:Protein Processing, Post-Translational
chemical_list: D009245:NADH Dehydrogenase; D017868:Cyclic AMP-Dependent Protein Kinases; D042967:Electron Transport Complex I; C427643:NDUFS4 protein, human