title: 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.
authors.affiliation: Metabolic Unit, Department of Medical Genetics, Sart-Tilman University Hospital, Liège, Belgium. fg.debray@chu.ulg.ac.be.
authors.forename: François-Guillaume
authors.initials: FG
authors.lastname: Debray
authors.affiliation: Institut für Zytobiologie und Zytopathologie, Philipps-Universität, Marburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stümpfig
authors.affiliation: Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Gent University Hospital, Gent, Belgium.
authors.forename: Arnaud V
authors.initials: AV
authors.lastname: Vanlander
authors.affiliation: Metabolic Unit, Department of Medical Genetics, Sart-Tilman University Hospital, Liège, Belgium.
authors.forename: Vinciane
authors.initials: V
authors.lastname: Dideberg
authors.affiliation: GIGA Research, Human Genetics Unit, University of Liège, Liège, Belgium.
authors.forename: Claire
authors.initials: C
authors.lastname: Josse
authors.affiliation: Metabolic Unit, Department of Medical Genetics, Sart-Tilman University Hospital, Liège, Belgium.
authors.forename: Jean-Hubert
authors.initials: JH
authors.lastname: Caberg
authors.affiliation: Metabolic Unit, Department of Medical Genetics, Sart-Tilman University Hospital, Liège, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Boemer
authors.affiliation: Metabolic Unit, Department of Medical Genetics, Sart-Tilman University Hospital, Liège, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Bours
authors.affiliation: Department of Pediatrics, Clinique de l'Espérance, Liège, Belgium.
authors.forename: René
authors.initials: R
authors.lastname: Stevens
authors.affiliation: Center of Medical Genetics, UZ Brussel and Reproduction and Genetics, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Seneca
authors.affiliation: Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Gent University Hospital, Gent, Belgium.
authors.forename: Joél
authors.initials: J
authors.lastname: Smet
authors.affiliation: Institut für Zytobiologie und Zytopathologie, Philipps-Universität, Marburg, Germany. lill@staff.uni-marburg.de.|LOEWE Zentrum für Synthetische Mikrobiologie SynMikro, Philipps-Universität, Marburg, Germany. lill@staff.uni-marburg.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Lill
authors.affiliation: Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Gent University Hospital, Gent, Belgium. Rudy.VanCoster@UGent.be.
authors.forename: Rudy
authors.initials: R
authors.lastname: van Coster
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics; D017809:Fatal Outcome; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D056784:Leukoencephalopathies / Q000175:diagnosis* / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008928:Mitochondria / Q000235:genetics; D028361:Mitochondrial Diseases / Q000175:diagnosis*; D009154:Mutation; D010641:Phenotype
chemical_list: D002352:Carrier Proteins; C585465:IBA57 protein, human; D007506:Iron-Sulfur Proteins; D042967:Electron Transport Complex I