A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure

Pascale De Lonlay, Isabelle Valnot, Antoni Barrientos, Marina Gorbatyuk, Alexander Tzagoloff, Jan Willem Taanman, Emmanuel Benayoun, Dominique Chrétien, Noman Kadhom, Anne Lombès, Hélène Ogier De Baulny, Patrick Niaudet, Arnold Munnich, Pierre Rustin, Agnès Rötig

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229 Scopus citations

Abstract

Complex III (CIII; ubiquinol cytochrome c reductase of the mitochondrial respiratory chain) catalyzes electron transfer from succinate and nicotinamide adenine dinucleotide-linked dehydrogenases to cytochrome c. CIII is made up of 11 subunits, of which all but one (cytochrome b) are encoded by nuclear DNA. CIII deficiencies are rare and manifest heterogeneous clinical presentations. Although pathogenic mutations in the gene encoding mitochondrial cytochrome b have been described, mutations in the nuclear-DNA-encoded subunits have not been reported. Involvement of various genes has been indicated in assembly of yeast CIII (refs. 8-11). So far only one such gene, BCS1L, has been identified in human. BCS1L represents, therefore, an obvious candidate gene in CIII deficiency. Here, we report BCS1L mutations in six patients, from four unrelated families and presenting neonatal proximal tubulopathy, hepatic involvement and encephalopathy. Complementation study in yeast confirmed the deleterious effect of these mutations. Mutation of BCS1L would seem to be a frequent cause of CIII deficiency, as one-third of our patients have BCS1L mutations.

Original languageEnglish (US)
Pages (from-to)57-60
Number of pages4
JournalNature genetics
Volume29
Issue number1
DOIs
StatePublished - Sep 12 2001
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    De Lonlay, P., Valnot, I., Barrientos, A., Gorbatyuk, M., Tzagoloff, A., Taanman, J. W., Benayoun, E., Chrétien, D., Kadhom, N., Lombès, A., De Baulny, H. O., Niaudet, P., Munnich, A., Rustin, P., & Rötig, A. (2001). A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nature genetics, 29(1), 57-60. https://doi.org/10.1038/ng706