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.
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Acknowledgments
This work was supported by a Fund Invest for Scientific Research (FIRS) (grant number 4709) from the Centre Hospitalier Universitaire de Liège, Belgium. We gratefully acknowledge the donation of the promotor-truncated versions of plasmid pEGFP-N1 from Dr. G.W. Mayr, Hamburg. RL acknowledges generous financial support from Deutsche Forschungsgemeinschaft (SFB 593, GRK 1216, and SPP 1710), and the LOEWE program of state Hessen. This work was also supported by the Special Research Fund (BOF) from the Ghent University (grant number B/00559/0).
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All procedures followed were in accordance with the ethical standards of the responsiblecommittee on human experimentation and with the Helsinki Declaration of 1975, as revised in2000. Written informed consent was obtained for patients being included in this study.
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Communicated by: Jerry Vockley
François-Guillaume Debray, Claudia Stümpfig and Arnaud V. Vanlander contributed equally to this work.
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Debray, FG., Stümpfig, C., Vanlander, A.V. et al. Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy. J Inherit Metab Dis 38, 1147–1153 (2015). https://doi.org/10.1007/s10545-015-9857-1
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DOI: https://doi.org/10.1007/s10545-015-9857-1