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Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy

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Abstract
Leukodystrophies are a heterogeneous group of severe genetic neurodegenerative disorders. A multiple mitochondrial dysfunctions syndrome was found in an infant presenting with a progressive leukoencephalopathy. Homozygosity mapping, whole exome sequencing, and functional studies were used to define the underlying molecular defect. Respiratory chain studies in skeletal muscle isolated from the proband revealed a combined deficiency of complexes I and II. In addition, western blotting indicated lack of protein lipoylation. The combination of these findings was suggestive for a defect in the iron-sulfur (Fe/S) protein assembly pathway. SNP array identified loss of heterozygosity in large chromosomal regions, covering the NFU1 and BOLA3, and the IBA57 and ABCB10 candidate genes, in 2p15-p11.2 and 1q31.1-q42.13, respectively. A homozygous c.436C > T (p.Arg146Trp) variant was detected in IBA57 using whole exome sequencing. Complementation studies in a HeLa cell line depleted for IBA57 showed that the mutant protein with the semi-conservative amino acid exchange was unable to restore the biochemical phenotype indicating a loss-of-function mutation of IBA57. In conclusion, defects in the Fe/S protein assembly gene IBA57 can cause autosomal recessive neurodegeneration associated with progressive leukodystrophy and fatal outcome at young age. In the affected patient, the biochemical phenotype was characterized by a defect in the respiratory chain complexes I and II and a decrease in mitochondrial protein lipoylation, both resulting from impaired assembly of Fe/S clusters.
Keywords
MAMMALIAN-CELLS, PROTEIN BIOGENESIS, HUMAN-DISEASE, MITOCHONDRIAL, NFU1, DEFICIENCY, MATURATION, LEUKOENCEPHALOPATHY, METABOLISM, ENZYMES

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Chicago
Debray, François-Guillaume, Claudia Stümpfig, ARNAUD VANLANDER, Vinciane Dideberg, Claire Josse, Jean-Hubert Caberg, François Boemer, et al. 2015. “Mutation of the Iron-sulfur Cluster Assembly Gene IBA57 Causes Fatal Infantile Leukodystrophy.” Journal of Inherited Metabolic Disease 38 (6): 1147–1153.
APA
Debray, F.-G., Stümpfig, C., VANLANDER, A., Dideberg, V., Josse, C., Caberg, J.-H., Boemer, F., et al. (2015). Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy. JOURNAL OF INHERITED METABOLIC DISEASE, 38(6), 1147–1153.
Vancouver
1.
Debray F-G, Stümpfig C, VANLANDER A, Dideberg V, Josse C, Caberg J-H, et al. Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy. JOURNAL OF INHERITED METABOLIC DISEASE. 2015;38(6):1147–53.
MLA
Debray, François-Guillaume, Claudia Stümpfig, ARNAUD VANLANDER, et al. “Mutation of the Iron-sulfur Cluster Assembly Gene IBA57 Causes Fatal Infantile Leukodystrophy.” JOURNAL OF INHERITED METABOLIC DISEASE 38.6 (2015): 1147–1153. Print.
@article{6852419,
  abstract     = {Leukodystrophies are a heterogeneous group of severe genetic neurodegenerative disorders. A multiple mitochondrial dysfunctions syndrome was found in an infant presenting with a progressive leukoencephalopathy. Homozygosity mapping, whole exome sequencing, and functional studies were used to define the underlying molecular defect. Respiratory chain studies in skeletal muscle isolated from the proband revealed a combined deficiency of complexes I and II. In addition, western blotting indicated lack of protein lipoylation. The combination of these findings was suggestive for a defect in the iron-sulfur (Fe/S) protein assembly pathway. SNP array identified loss of heterozygosity in large chromosomal regions, covering the NFU1 and BOLA3, and the IBA57 and ABCB10 candidate genes, in 2p15-p11.2 and 1q31.1-q42.13, respectively. A homozygous c.436C\,{\textrangle}\,T (p.Arg146Trp) variant was detected in IBA57 using whole exome sequencing. Complementation studies in a HeLa cell line depleted for IBA57 showed that the mutant protein with the semi-conservative amino acid exchange was unable to restore the biochemical phenotype indicating a loss-of-function mutation of IBA57. In conclusion, defects in the Fe/S protein assembly gene IBA57 can cause autosomal recessive neurodegeneration associated with progressive leukodystrophy and fatal outcome at young age. In the affected patient, the biochemical phenotype was characterized by a defect in the respiratory chain complexes I and II and a decrease in mitochondrial protein lipoylation, both resulting from impaired assembly of Fe/S clusters.},
  author       = {Debray, Fran\c{c}ois-Guillaume and St{\"u}mpfig, Claudia and Vanlander, Arnaud and Dideberg, Vinciane and Josse, Claire and Caberg, Jean-Hubert and Boemer, Fran\c{c}ois and Bours, Vincent and Stevens, Ren{\'e} and Seneca, Sara and Smet, Jo{\'e}l and Lill, Roland and Van Coster, Rudy},
  issn         = {0141-8955},
  journal      = {JOURNAL OF INHERITED METABOLIC DISEASE},
  keyword      = {MAMMALIAN-CELLS,PROTEIN BIOGENESIS,HUMAN-DISEASE,MITOCHONDRIAL,NFU1,DEFICIENCY,MATURATION,LEUKOENCEPHALOPATHY,METABOLISM,ENZYMES},
  language     = {eng},
  number       = {6},
  pages        = {1147--1153},
  title        = {Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy},
  url          = {http://dx.doi.org/10.1007/s10545-015-9857-1},
  volume       = {38},
  year         = {2015},
}

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