Article

Mutated NDUFS6 is the cause of fatal neonatal lactic acidemia in Caucasus Jews.

Genetic Institute, Ha'Emek Medical Center, Afula, Rappaport School of Medicine, Technion, Haifa, Israel.
European journal of human genetics: EJHG (impact factor: 3.56). 03/2009; 17(9):1200-3. DOI:10.1038/ejhg.2009.24 pp.1200-3
Source: PubMed

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.

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Keywords

45 proteins
 
c.344G>A homozygous mutation
 
diverse homozygous mutations
 
energy generation disorders
 
evolutionary conserved cysteine residue
 
fatal neonatal lactic acidemia
 
humans
 
identical haplotype
 
largest respiratory chain complex
 
lethal neonatal lactic acidemia
 
Mb region
 
mitochondrial inner membrane
 
NDUFS6 mitochondrial complex
 
NDUFS6 mutation
 
NDUFS6 sequence
 
nuclear gene encoding
 
similar phenotype
 
unrelated families
 
variable consequential NDUFS6 protein defects
 
Whole genome homozygosity