Advanced search
1 file | 679.89 KB

Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy

(2013) HUMAN MOLECULAR GENETICS. 22(13). p.2590-2602
Author
Organization
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.
Keywords
iron-sulfur clusters, IBA57, RESPIRATORY-CHAIN, PROTEIN BIOGENESIS, LACTIC-ACIDOSIS, ISA2 PROTEINS, METABOLISM, MATURATION, MITOCHONDRIA, DEFICIENCY, DISEASE, DEFECT

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 679.89 KB

Citation

Please use this url to cite or link to this publication:

Chicago
Ajit Bolar, Nikhita, Arnaud Vanlander, Claudia Wilbrecht, Nathalie Van der Aa, Joél Smet, Boel De Paepe, Geert Vandeweyer, et al. 2013. “Mutation of the Iron-sulfur Cluster Assembly Gene IBA57 Causes Severe Myopathy and Encephalopathy.” Human Molecular Genetics 22 (13): 2590–2602.
APA
Ajit Bolar, N., Vanlander, A., Wilbrecht, C., Van der Aa, N., Smet, J., De Paepe, B., Vandeweyer, G., et al. (2013). Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy. HUMAN MOLECULAR GENETICS, 22(13), 2590–2602.
Vancouver
1.
Ajit Bolar N, Vanlander A, Wilbrecht C, Van der Aa N, Smet J, De Paepe B, et al. Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy. HUMAN MOLECULAR GENETICS. 2013;22(13):2590–602.
MLA
Ajit Bolar, Nikhita, Arnaud Vanlander, Claudia Wilbrecht, et al. “Mutation of the Iron-sulfur Cluster Assembly Gene IBA57 Causes Severe Myopathy and Encephalopathy.” HUMAN MOLECULAR GENETICS 22.13 (2013): 2590–2602. Print.
@article{3223478,
  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 {\textrangle} 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.},
  author       = {Ajit Bolar, Nikhita and Vanlander, Arnaud and Wilbrecht, Claudia and Van der Aa, Nathalie and Smet, Jo{\'e}l and De Paepe, Boel and Vandeweyer, Geert and Kooy, Frank and Eyskens, Fran\c{c}ois and De Latter, Elien and Delanghe, Gwenda and Govaert, Paul and Leroy, Juliaan and Loeys, Bart and Lill, Roland and Van Laer, Lut and Van Coster, Rudy},
  issn         = {0964-6906},
  journal      = {HUMAN MOLECULAR GENETICS},
  language     = {eng},
  number       = {13},
  pages        = {2590--2602},
  title        = {Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy},
  url          = {http://dx.doi.org/10.1093/hmg/ddt107},
  volume       = {22},
  year         = {2013},
}

Altmetric
View in Altmetric
Web of Science
Times cited: