GRACILE syndrome,a lethal metabolic disorder with iron overload,is caused by a point mutation in BCS1L |
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Authors: | Visapää Ilona Fellman Vineta Vesa Jouni Dasvarma Ayan Hutton Jenna L Kumar Vijay Payne Gregory S Makarow Marja Van Coster Rudy Taylor Robert W Turnbull Douglass M Suomalainen Anu Peltonen Leena |
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Institution: | 1 Department of Human Genetics, University of California Los Angeles School of Medicine, Los Angeles 2 Department of Biological Chemistry, University of California Los Angeles School of Medicine, Los Angeles 3 Department of Molecular Medicine, National Public Health Institute, University of Helsinki, Helsinki 4 Department of Medical Genetics, University of Helsinki, Helsinki 5 Institute of Biotechnology, University of Helsinki, Helsinki 6 Department of Neurology and Programme of Neurosciences, University of Helsinki, Helsinki 7 Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki 8 Murdoch Children’s Research Institute, Melbourne, Australia 9 Department of Pediatrics, Ghent University Hospital, Ghent, Belgium 10 Department of Neurology, University of Newcastle upon Tyne, Newcastle, United Kingdom |
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Abstract: | GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death) syndrome is a recessively inherited lethal disease characterized by fetal growth retardation, lactic acidosis, aminoaciduria, cholestasis, and abnormalities in iron metabolism. We previously localized the causative gene to a 1.5-cM region on chromosome 2q33-37. In the present study, we report the molecular defect causing this metabolic disorder, by identifying a homozygous missense mutation that results in an S78G amino acid change in the BCS1L gene in Finnish patients with GRACILE syndrome, as well as five different mutations in three British infants. BCS1L, a mitochondrial inner-membrane protein, is a chaperone necessary for the assembly of mitochondrial respiratory chain complex III. Pulse-chase experiments performed in COS-1 cells indicated that the S78G amino acid change results in instability of the polypeptide, and yeast complementation studies revealed a functional defect in the mutated BCS1L protein. Four different mutations in the BCS1L gene have been reported elsewhere, in Turkish patients with a distinctly different phenotype. Interestingly, the British and Turkish patients had complex III deficiency, whereas in the Finnish patients with GRACILE syndrome complex III activity was within the normal range, implying that BCS1L has another cellular function that is uncharacterized but essential and is putatively involved in iron metabolism. |
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