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.344G4A 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.

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy

“…Compared with NDUFS6 patients who die within the first week of life, Ndufs6 gt/gt mice can survive for more than 4 mo, presumably because the CI deficiency is heart specific rather than systemic, and cardiac adaptation may be possible until reserve capacity is ultimately lost. All NDUFS6 patients (except one) diagnosed so far did not have a specific cardiac assessment due to the system-wide severity of the disease causing early death (18,19). Hence, cardiac involvement in these patients cannot be excluded.…”

“…A brain-specific Ndufs4 knockout showed a nearly identical phenotype to the systemic knockout with death by 7 wk (17). These are useful models but do not develop the characteristic neuropathology of Leigh syndrome and the early lethality means they can only be used in short-term treatment studies.We and others have described children with mutations in the NDUFS6 subunit gene (18,19), all of whom died in the first month of life. The NDUFS6 gene is in the second most conserved…”

“…We and others have described children with mutations in the NDUFS6 subunit gene (18,19), all of whom died in the first month of life. The NDUFS6 gene is in the second most conserved group of CI subunit genes (14) and all patients had null-type mutations.…”

Accessory NUMM (NDUFS6) subunit harbors a Zn-binding site and is essential for biogenesis of mitochondrial complex I

“…Mutation of H110 was better tolerated than mutation of C125, whereas exchange of C128 had the strongest effect. Notably, mutation of C115 in human complex I subunit NDUFS6, corresponding to C128 of NUMM of Y. lipolytica, was identified to cause fatal neonatal lactic acidosis (15). The consistent lack of NUMM and presence of N7BML in form P2 found in the three investigated site-directed mutants suggests that a functional metal binding site is required for proper folding and association of the subunit with the nascent enzyme complex.…”

“…A poly-alanine model of the orthologous 13-kDa subunit was tentatively fitted into the electron microscopic structure of bovine complex I but Zn binding was not shown (5). In human, mutations leading to the loss of the orthologous NDUFS6 subunit or exchange of one of the three conserved cysteine residues were shown to cause fatal diseases (14,15). A mouse model to study complex I-linked diseases was generated by knock down of the corresponding gene (16).…”