NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency

Abstract

Complex I deficiency, the most common respiratory chain defect, is genetically heterogeneous: mutations in 8 nuclear and 7 mitochondrial DNA genes encoding complex I subunits have been described. However, these genes account for disease in only a minority of complex I-deficient patients. We investigated whether there may be an unknown common gene by performing functional complementation analysis of cell lines from 10 unrelated patients. Two of the patients were found to have mitochondrial DNA mutations. The other 8 represented 7 different (nuclear) complementation groups, all but 1 of which showed abnormalities of complex I assembly. It is thus unlikely that any one unknown gene accounts for a large proportion of complex I cases. The 2 patients sharing a nuclear complementation group had a similar abnormal complex I assembly profile and were studied further by homozygosity mapping, chromosome transfers, and microarray expression analysis. NDUFS6, a complex I subunit gene not previously associated with complex I deficiency, was grossly underexpressed in the 2 patient cell lines. Both patients had homozygous mutations in this gene, one causing a splicing abnormality and the other a large deletion. This integrated approach to gene identification offers promise for identifying other unknown causes of respiratory chain disorders.

Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart

“…Seven of the subunits of Complex I are encoded by the mitochondrial genome, while the remaining 39 subunits are products of nuclear genes. Mutations identified in genes encoding for complex I subunits have been associated with complex I disassembly, instability and increase in reactive oxygen species production, resulting in degenerative diseases (Benit et al, 2003;Kirby et al, 2004;Loeffen et al, 2001;Mamelak et al, 2005). In the present study no significant alteration in expression of the mtDNA coded genes that are included in the Affymetrix Rat Genome 230 2.0 were found, whereas expression of 16 out of the 37 genes coded by the nDNA was decreased.…”

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

“…Mutations in the NDUFS6 gene were previously identified in only two patients. 19 Similar to our patients, they presented with fatal infantile lactic acidemia, suggesting that analysis of NDUFS6 sequence should be considered in patients presenting with lethal neonatal lactic acidemia and isolated complex I deficiency.…”

“…Although the mutations described previously were deleterious (splice site mutation resulting in a frame shift and a large genomic deletion), fully assembled 900 kDa complex I was formed along with a smaller B750 kDa subassembly intermediate. 19 This complex I subassembly was shown to be associated with complex III in a supercomplex with a smaller molecular weight compared with that found in normal mitochondria. 20 Normally assembled complex I was generated on reintroduction of NDUFS6 into mitochondria of NDUFS6-deficient patients suggesting that NDUFS6 is involved in the final stage of the modular process of complex I assembly.…”

NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease

“…However, genes encoding accessory subunits, such as NDUFS4, NDUFS6, NDUFA1, NDUFA2, and NDUFA11, may also contain pathogenic mutations. [8][9][10]29,30 NDUFA10 also belongs to these accessory subunits.…”