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 re spiratory chain) catalyzes electron transfer from succinate and nicotinamid e adenine dinucleotide-linked dehydrogenases to cytochrome c. CIII is made up of 11 subunits, of which all but one (cytochrome b) are encoded by nucle ar DNA. CIII deficiencies are rare and manifest heterogeneous clinical pres entations(1,2). Although pathogenic mutations in the gene encoding mitochon drial cytochrome b have been described(3-7), mutations in the nuclear-DNA-e ncoded subunits have not been reported. Involvement of various genes has be en indicated in assembly of yeast CIII (refs. 8-11). So far only one such g ene, BCS1L, has been identified in human(12). BCS1L represents, therefore, an obvious candidate gene in CIII deficiency. Here,we report BCS1L mutation s in six patients, from four unrelated families and presenting neonatal pro ximal tubulopathy, hepatic involvement and encephalopathy. Complementation study in yeast confirmed the deleterious effect of these mutations. Mutatio n of BCS1L would seem to be a frequent cause of CIII deficiency, as one-thi rd of our patients have BCS1L mutations.