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

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.

Clinical and genetic aspects of defects in the mitochondrial iron–sulfur cluster synthesis pathway

“…Cerebral MRI in one subject showed, aside from bilateral optic nerve atrophy, scattered white matter alterations. Only one subject presented with mild cerebellar and cervical spinal cord atrophy [61]. …”

“…These findings correlated with extensive white matter alterations in cerebrum, cerebellum, mesencephalon and in the upper spinal cord. The corpus callosum and basal ganglia were not affected [61–63]. …”

Mammalian Fe–S proteins: definition of a consensus motif recognized by the co-chaperone HSC20

“…Consistent with the proposed role of ISCA1/ISCA2 and IBA57 in the biogenesis of [Fe4-S4] clusters for a subset of mitochondrial proteins, a mutation affecting the stability of IBA57 was found in two patients with severe myopathy and encephalopathy associated with compromised activities of the lipoic acid dependent enzymes, indicating defective maturation of LIAS 109 . A loss of function mutation in IBA57 was recently identified in a patient affected by infantile leukodystrophy with lack of protein lipoylation and decreased complex I and II activities 162 . In most cases, the conclusion that an intermediate carrier protein has specific downstream recipients is based on broad inferences rather than on direct experimental data.…”

Role of Nfu1 and Bol3 in iron-sulfur cluster transfer to mitochondrial clients

“…A severe syndrome characterized by the dysfunction of multiple mitochondrial enzymes has been described for a series of patients with mutations in four mitochondrial proteins IBA57, ISCA2, NFU1 and BOLA3 (Seyda et al, 2001; Cameron et al, 2011; Navarro-Sastre et al, 2011; Ferrer-Cortès et al, 2013; Nizon et al, 2014; Baker et al, 2014; Debray et al, 2015; Lossos et al, 2015; Al-Hassnan et al, 2015). Patients with this Multiple Mitochondria Dysfunctions Syndrome (MMDS) are afflicted with lactic acidosis, nonketotic hyperglycinemia and infantile encephalopathy typically leading to death in their first year of life.…”