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J Inherit Metab Dis. 2015 Nov;38(6):1147-53. doi: 10.1007/s10545-015-9857-1. Epub 2015 May 14.

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

Author information

1
Metabolic Unit, Department of Medical Genetics, Sart-Tilman University Hospital, Liège, Belgium. fg.debray@chu.ulg.ac.be.
2
Institut für Zytobiologie und Zytopathologie, Philipps-Universität, Marburg, Germany.
3
Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Gent University Hospital, Gent, Belgium.
4
Metabolic Unit, Department of Medical Genetics, Sart-Tilman University Hospital, Liège, Belgium.
5
GIGA Research, Human Genetics Unit, University of Liège, Liège, Belgium.
6
Department of Pediatrics, Clinique de l'Espérance, Liège, Belgium.
7
Center of Medical Genetics, UZ Brussel and Reproduction and Genetics, Vrije Universiteit Brussel, Brussels, Belgium.
8
Institut für Zytobiologie und Zytopathologie, Philipps-Universität, Marburg, Germany. lill@staff.uni-marburg.de.
9
LOEWE Zentrum für Synthetische Mikrobiologie SynMikro, Philipps-Universität, Marburg, Germany. lill@staff.uni-marburg.de.
10
Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Gent University Hospital, Gent, Belgium. Rudy.VanCoster@UGent.be.

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.

PMID:
25971455
DOI:
10.1007/s10545-015-9857-1
[Indexed for MEDLINE]

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