TY - JOUR
T1 - A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure
AU - De Lonlay, Pascale
AU - Valnot, Isabelle
AU - Barrientos, Antoni
AU - Gorbatyuk, Marina
AU - Tzagoloff, Alexander
AU - Taanman, Jan Willem
AU - Benayoun, Emmanuel
AU - Chrétien, Dominique
AU - Kadhom, Noman
AU - Lombès, Anne
AU - De Baulny, Hélène Ogier
AU - Niaudet, Patrick
AU - Munnich, Arnold
AU - Rustin, Pierre
AU - Rötig, Agnès
N1 - Funding Information:
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.).
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
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U2 - 10.1038/ng706
DO - 10.1038/ng706
M3 - Article
C2 - 11528392
AN - SCOPUS:17944381521
VL - 29
SP - 57
EP - 60
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 1
ER -