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

Lookup NU author(s): Dr Denise Kirby, Professor Robert Taylor

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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 farther 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.


Publication metadata

Author(s): Kirby DM, Salemi R, Sugiana C, Ohtake A, Parry L, Bell KM, Kirk EP, Boneh A, Taylor RW, Dahl H-HM, Ryan MT, Thorburn DR

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2004

Volume: 114

Issue: 6

Pages: 837-845

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation

URL: http://dx.doi.org/10.1172/JCI200420683

DOI: 10.1172/JCI200420683

PubMed id: 15372108


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