title: 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.
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Kirby
authors.forename: Renato
authors.initials: R
authors.lastname: Salemi
authors.forename: Canny
authors.initials: C
authors.lastname: Sugiana
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.forename: Lee
authors.initials: L
authors.lastname: Parry
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Bell
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Kirk
authors.forename: Avihu
authors.initials: A
authors.lastname: Boneh
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Hans-Henrik M
authors.initials: HH
authors.lastname: Dahl
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ryan
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002459:Cell Fusion; D002460:Cell Line; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D005816:Genetic Complementation Test; D006801:Humans; D007773:Lactates / Q000097:blood; D008297:Male; D009154:Mutation / Q000235:genetics*; D009245:NADH Dehydrogenase; D010375:Pedigree
chemical_list: D004272:DNA, Mitochondrial; D007773:Lactates; D009245:NADH Dehydrogenase; C493878:NDUFS6 protein, human; D042967:Electron Transport Complex I