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Mutation of the iron‐sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy
Author(s) -
Debray FrançoisGuillaume,
Stümpfig Claudia,
Vanlander Arnaud V.,
Dideberg Vinciane,
Josse Claire,
Caberg JeanHubert,
Boemer François,
Bours Vincent,
Stevens René,
Seneca Sara,
Smet Joél,
Lill Roland,
Coster Rudy
Publication year - 2015
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-015-9857-1
Subject(s) - biology , genetics , leukodystrophy , compound heterozygosity , exome sequencing , mutation , respiratory chain , disease gene identification , mitochondrial respiratory chain , loss of heterozygosity , phenotype , proband , gene , mitochondrion , allele , medicine , pathology , disease
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.