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

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


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics*
  • Electron Transport Complex I / genetics
  • Fatal Outcome
  • Heterozygote
  • Homozygote
  • Humans
  • Infant
  • Iron-Sulfur Proteins / genetics*
  • Leukoencephalopathies / diagnosis*
  • Leukoencephalopathies / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Mitochondria / genetics
  • Mitochondrial Diseases / diagnosis*
  • Mutation
  • Phenotype


  • Carrier Proteins
  • IBA57 protein, human
  • Iron-Sulfur Proteins
  • Electron Transport Complex I

Supplementary concepts

  • Multiple Mitochondrial Dysfunctions Syndrome