title: Mutated NDUFS6 is the cause of fatal neonatal lactic acidemia in Caucasus Jews.
abstract: NADH:ubiquinone oxidoreductase (complex I; EC 1.6.5.3), the largest respiratory chain complex is composed of 45 proteins and is located at the mitochondrial inner membrane. Defects in complex I are associated with energy generation disorders, of which the most severe is congenital lactic acidosis. We report on four infants from two unrelated families of Jewish Caucasus origin with fatal neonatal lactic acidemia due to isolated complex I deficiency. Whole genome homozygosity mapping, identified a 2.6 Mb region of identical haplotype in the affected babies. Sequence analysis of the nuclear gene encoding for the NDUFS6 mitochondrial complex I subunit located within this region identified the c.344G>A homozygous mutation resulting in substitution of a highly evolutionary conserved cysteine residue by tyrosine. This is the second report of NDUFS6 mutation in humans. Both reports describe three diverse homozygous mutations with variable consequential NDUFS6 protein defects that result in similar phenotype. Our study further emphasizes that NDUFS6 sequence should be analyzed in patients presenting with lethal neonatal lactic acidemia due to isolated complex I deficiency.
authors.affiliation: Genetic Institute, Ha'Emek Medical Center, Afula, Rappaport School of Medicine, Technion, Haifa, Israel. spiegelr@zahav.net.il
authors.forename: Ronen
authors.initials: R
authors.lastname: Spiegel
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.forename: Dan
authors.initials: D
authors.lastname: Reich
authors.forename: Marina
authors.initials: M
authors.lastname: Penyakov
authors.forename: Yasir
authors.initials: Y
authors.lastname: Hujeirat
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.forename: Stavit A
authors.initials: SA
authors.lastname: Shalev
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D007585:Jews / Q000235:genetics; D008297:Male; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics*
chemical_list: D009245:NADH Dehydrogenase; C493878:NDUFS6 protein, human