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


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 presentations1,2. Although pathogenic mutations in the gene encoding mitochondrial cytochrome b have been described3,4,5,6,7, mutations in the nuclear-DNA-encoded subunits have not been reported. Involvement of various genes has been indicated in assembly of yeast CIII (refs. 811). So far only one such gene, BCS1L, has been identified in human12. 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.

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Figure 1: Genomic structure and sequence analysis of BCS1L.
Figure 2: Growth of BCS1-null mutants and transformants on rich medium (yeast extract and peptone) containing glycerol as the carbon source.

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We thank J.M. Saudubray and C. Debauche for referring patients 5 and 6 to us. We thank M. Glerum for her gifts of pMGL3, a YEp351 shuttle plasmid with the ADH1 promoter and terminator, and pBCS1H, a cDNA clone containing human BCS1L on a 1.5-kb BamHI fragment. We thank C. Dodé, who provided us the DNA of control individuals from Turkish origin. This research was supported in part by the Association Française contre les Myopathies (7145-AO99), by a research grant from the National Institutes of Health HL22174 (to A.T.) and by grant MDACU01991001 from the Muscular Dystrophy Association (to A.B.).

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Correspondence to Agnès Rötig.

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de Lonlay, P., Valnot, I., Barrientos, A. et al. A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nat Genet 29, 57–60 (2001). https://doi.org/10.1038/ng706

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