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

Kirby, Denise M., Salemi, Renato, Sugiana, Canny, Ohtake, Akira, Parry, Lee ORCID: https://orcid.org/0000-0002-4467-9196, Bell, Katrina M., Kirk, Edwin P., Boneh, Avihu, Taylor, Robert W., Dahl, Hans-Henrik M., Ryan, Michael T. and Thorburn, David R. 2004. NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. The Journal of Clinical Investigation 114 (6) , pp. 837-845. 10.1172/JCI200420683

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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 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Subjects:	Q Science > QH Natural history > QH426 Genetics
Additional Information:	Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/0021-9738/ (accessed 24/02/2014)
Publisher:	American Society for Clinical Investigation
ISSN:	0021-9738
Date of First Compliant Deposit:	30 March 2016
Last Modified:	16 May 2023 11:59
URI:	https://orca.cardiff.ac.uk/id/eprint/47423

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