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

François-Guillaume Debray, Claudia Stümpfig, Arnaud Vanlander (UGent) , Vinciane Dideberg, Claire Josse, Jean-Hubert Caberg, François Boemer, Vincent Bours, René Stevens, Sara Seneca, et al.
(2015) JOURNAL OF INHERITED METABOLIC DISEASE. 38(6). p.1147-1153
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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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MLA
Debray, François-Guillaume, et al. “Mutation of the Iron-Sulfur Cluster Assembly Gene IBA57 Causes Fatal Infantile Leukodystrophy.” JOURNAL OF INHERITED METABOLIC DISEASE, vol. 38, no. 6, 2015, pp. 1147–53, doi:10.1007/s10545-015-9857-1.
APA
Debray, F.-G., Stümpfig, C., Vanlander, A., Dideberg, V., Josse, C., Caberg, J.-H., … Van Coster, R. (2015). Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy. JOURNAL OF INHERITED METABOLIC DISEASE, 38(6), 1147–1153. https://doi.org/10.1007/s10545-015-9857-1
Chicago author-date
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): 1147–53. https://doi.org/10.1007/s10545-015-9857-1.
Chicago author-date (all authors)
Debray, François-Guillaume, Claudia Stümpfig, Arnaud Vanlander, Vinciane Dideberg, Claire Josse, Jean-Hubert Caberg, François Boemer, Vincent Bours, René Stevens, Sara Seneca, Joél Smet, Roland Lill, and Rudy Van Coster. 2015. “Mutation of the Iron-Sulfur Cluster Assembly Gene IBA57 Causes Fatal Infantile Leukodystrophy.” JOURNAL OF INHERITED METABOLIC DISEASE 38 (6): 1147–1153. doi:10.1007/s10545-015-9857-1.
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.
IEEE
[1]
F.-G. Debray et al., “Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy,” JOURNAL OF INHERITED METABOLIC DISEASE, vol. 38, no. 6, pp. 1147–1153, 2015.
@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 > 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, François-Guillaume and Stümpfig, Claudia and Vanlander, Arnaud and Dideberg, Vinciane and Josse, Claire and Caberg, Jean-Hubert and Boemer, François and Bours, Vincent and Stevens, René and Seneca, Sara and Smet, Joél and Lill, Roland and Van Coster, Rudy}},
  issn         = {{0141-8955}},
  journal      = {{JOURNAL OF INHERITED METABOLIC DISEASE}},
  keywords     = {{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://doi.org/10.1007/s10545-015-9857-1}},
  volume       = {{38}},
  year         = {{2015}},
}
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