title: Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy.
abstract: Two siblings from consanguineous parents died perinatally with a condition characterized by generalized hypotonia, respiratory insufficiency, arthrogryposis, microcephaly, congenital brain malformations and hyperglycinemia. Catalytic activities of the mitochondrial respiratory complexes I and II were deficient in skeletal muscle, a finding suggestive of an inborn error in mitochondrial biogenesis. Homozygosity mapping identified IBA57 located in the largest homozygous region on chromosome 1 as a culprit candidate gene. IBA57 is known to be involved in the biosynthesis of mitochondrial [4Fe-4S] proteins. Sequence analysis of IBA57 revealed the homozygous mutation c.941A > C, p.Gln314Pro. Severely decreased amounts of IBA57 protein were observed in skeletal muscle and cultured skin fibroblasts from the affected subjects. HeLa cells depleted of IBA57 showed biochemical defects resembling the ones found in patient-derived cells, including a decrease in various mitochondrial [4Fe-4S] proteins and in proteins covalently linked to lipoic acid (LA), a cofactor produced by the [4Fe-4S] protein LA synthase. The defects could be complemented by wild-type IBA57 and partially by mutant IBA57. As a result of the mutation, IBA57 protein was excessively degraded, an effect ameliorated by protease inhibitors. Hence, we propose that the mutation leads to partial functional impairment of IBA57, yet the major pathogenic impact is due to its proteolytic degradation below physiologically critical levels. In conclusion, the ensuing lethal complex biochemical phenotype of a novel metabolic syndrome results from multiple Fe/S protein defects caused by a deficiency in the Fe/S cluster assembly protein IBA57.
authors: Department of Medical Genetics, Faculty of Medicine and Health Sciences, University Hospital, University of Antwerp, Antwerp 2650, Belgium.
authors: Nikhita
authors: N
authors: Ajit Bolar
authors: Arnaud Vincent
authors: AV
authors: Vanlander
authors: Claudia
authors: C
authors: Wilbrecht
authors: Nathalie
authors: N
authors: Van der Aa
authors: Joél
authors: J
authors: Smet
authors: Boel
authors: B
authors: De Paepe
authors: Geert
authors: G
authors: Vandeweyer
authors: Frank
authors: F
authors: Kooy
authors: François
authors: F
authors: Eyskens
authors: Elien
authors: E
authors: De Latter
authors: Gwenda
authors: G
authors: Delanghe
authors: Paul
authors: P
authors: Govaert
authors: Jules Gerard
authors: JG
authors: Leroy
authors: Bart
authors: B
authors: Loeys
authors: Roland
authors: R
authors: Lill
authors: Lut
authors: L
authors: Van Laer
authors: Rudy
authors: R
authors: Van Coster
mesh_terms: D001921:Brain / Q000473:pathology; D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004579:Electron Transport / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009135:Muscular Diseases / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D035781:Siblings; D012867:Skin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C585465:IBA57 protein, human