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

Denise M. Kirby, Renato Salemi, Canny Sugiana, Akira Ohtake, Lee Parry, Katrina M. Bell, Edwin P. Kirk, Avihu Boneh, Robert W. Taylor, Hans Henrik M. Dahl, Michael T. Ryan, David R. Thorburn

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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.

Original languageEnglish
Pages (from-to)837-845
Number of pages9
JournalJournal of Clinical Investigation
Volume114
Issue number6
DOIs
Publication statusPublished - 1 Jan 2004
Externally publishedYes

Cite this

Kirby, D. M., Salemi, R., Sugiana, C., Ohtake, A., Parry, L., Bell, K. M., ... Thorburn, D. R. (2004). NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. Journal of Clinical Investigation, 114(6), 837-845. https://doi.org/10.1172/JCI20683
Kirby, Denise M. ; Salemi, Renato ; Sugiana, Canny ; Ohtake, Akira ; Parry, Lee ; Bell, Katrina M. ; Kirk, Edwin P. ; Boneh, Avihu ; Taylor, Robert W. ; Dahl, Hans Henrik M. ; Ryan, Michael T. ; Thorburn, David R. / NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. In: Journal of Clinical Investigation. 2004 ; Vol. 114, No. 6. pp. 837-845.
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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.",
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Kirby, DM, Salemi, R, Sugiana, C, Ohtake, A, Parry, L, Bell, KM, Kirk, EP, Boneh, A, Taylor, RW, Dahl, HHM, Ryan, MT & Thorburn, DR 2004, 'NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency', Journal of Clinical Investigation, vol. 114, no. 6, pp. 837-845. https://doi.org/10.1172/JCI20683

NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. / Kirby, Denise M.; Salemi, Renato; Sugiana, Canny; Ohtake, Akira; Parry, Lee; Bell, Katrina M.; Kirk, Edwin P.; Boneh, Avihu; Taylor, Robert W.; Dahl, Hans Henrik M.; Ryan, Michael T.; Thorburn, David R.

In: Journal of Clinical Investigation, Vol. 114, No. 6, 01.01.2004, p. 837-845.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Salemi, Renato

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AU - Ohtake, Akira

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AU - Bell, Katrina M.

AU - Kirk, Edwin P.

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AU - Ryan, Michael T.

AU - Thorburn, David R.

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N2 - 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.

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