Mutated NDUFS6 is the cause of fatal neonatal lactic acidemia in Caucasus Jews.
ABSTRACT NADH:ubiquinone oxidoreductase (complex I; EC 184.108.40.206), 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.
Article: Evaluation of enzymatic assays and compounds affecting ATP production in mitochondrial respiratory chain complex I deficiency.[show abstract] [hide abstract]
ABSTRACT: Isolated complex I deficiency is the most common oxidative phosphorylation defect and is associated with substantial morbidity and mortality. The diagnosis is made by enzymatic analysis and for most patients the molecular pathology remains undefined. Various cofactors and vitamins are frequently administered, but their efficacy have been difficult to assess. We employed determination of ATP production in fibroblast cell lines from patients with complex I deficiency to evaluate the usefulness of therapeutic agents. The effect of each additive varied among the different patients with certain agents favorably affecting ATP production rate in some of the patients and adversely affecting it in others. The reduced nicotinamide adenine dinucleotide (NADH)-ferricyanide reductase assay in muscle mitochondria correlated better than the NADH-coenzyme Q and NADH-cytochrome c assays with ATP production rate in fibroblasts. Our results underscore the necessity of evaluation of different agents for each patient separately. The NADH-ferricyanide reductase assay play a helpful role in directing mutation analysis and identifying patients which are more likely to have their cells amenable for ATP production assessment.Analytical Biochemistry 01/2005; 335(1):66-72. · 3.00 Impact Factor
Article: Mutations in the complex I NDUFS2 gene of patients with cardiomyopathy and encephalomyopathy.[show abstract] [hide abstract]
ABSTRACT: Human complex I is built up and regulated by genes encoded by the mitochondrial DNA (mtDNA) as well as the nuclear DNA (nDNA). In recent years, attention mainly focused on the relation between complex I deficiency and mtDNA mutations. However, a high percentage of consanguinity and an autosomal-recessive mode of inheritance observed within our patient group as well as the absence of common mtDNA mutations make a nuclear genetic cause likely. The NDUFS2 protein is part of complex I of many pro- and eukaryotes. The nuclear gene coding for this protein is therefore an important candidate for mutational detection studies in enzymatic complex I deficient patients. Screening of patient NDUFS2 cDNA by reverse transcriptase-polymerase chain reaction (RT-PCR) in combination with direct DNA sequencing revealed three missense mutations resulting in the substitution of conserved amino acids in three families.Annals of Neurology 03/2001; 49(2):195-201. · 11.09 Impact Factor
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ABSTRACT: Homozygosity mapping was performed in five patients from a consanguineous family who presented with infantile mitochondrial encephalomyopathy attributed to isolated NADH:ubiquinone oxidoreductase (complex I) deficiency. This resulted in the identification of a missense mutation in a conserved residue of the C6ORF66 gene, which encodes a 20.2 kDa mitochondrial protein. The mutation was also detected in a patient who presented with antenatal cardiomyopathy. In muscle of two patients, the levels of the C6ORF66 protein and of the fully assembled complex I were markedly reduced. Transfection of the patients' fibroblasts with wild-type C6ORF66 cDNA restored complex I activity. These data suggest that C6ORF66 is an assembly factor of complex I. Interestingly, the C6ORF66 gene product was previously shown to promote breast cancer cell invasiveness.The American Journal of Human Genetics 02/2008; 82(1):32-8. · 10.60 Impact Factor