2. Academic Validation
  3. Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia

Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia

  • Neurology. 2015 Feb 17;84(7):659-67. doi: 10.1212/WNL.0000000000001270.
Alexander Lossos 1,  Claudia Stümpfig 1,  Giovanni Stevanin 1,  Marion Gaussen 1,  Bat-El Zimmerman 1,  Emeline Mundwiller 1,  Moriya Asulin 1,  Liat Chamma 1,  Ruth Sheffer 1,  Adel Misk 1,  Shlomo Dotan 1,  John M Gomori 1,  Penina Ponger 1,  Alexis Brice 1,  Israela Lerer 1,  Vardiella Meiner 2,  Roland Lill 2
Affiliations

Affiliations

  • 1 From the Department of Neurology and Agnes Ginges Center for Human Neurogenetics (A.L., P.P.), Department of Genetics and Metabolic Diseases (B.-E.Z., M.A., L.C., R.S., I.L., V.M.), Neuro-Ophthalmology Center, Department of Ophthalmology (S.D.), and Department of Radiology (J.M.G.), Hebrew University-Hadassah Medical Center, Jerusalem, Israel; Institut für Zytobiologie und Zytopathologie (C.S., R.L.), Philipps-Universität Marburg, Germany; Laboratoire de Neurogénétique (G.S., M.G.), Ecole Pratique des Hautes Etudes-heSam Universite, Institut du Cerveau et de la Moelle épinière, Paris; Inserm U1127 (G.S., M.G., E.M., A.B.), CNRS UMR7225, Sorbonne Universites, UPMC Univ Paris 06 UMR_1127, Institut du Cerveau et de la Moelle epiniere, ICM, Paris; APHP (G.S., A.B.), Fédération de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris; Institut du Cerveau et de la Moelle épinière (G.S., E.M., A.B.), Genotyping and Sequencing Facility, Paris, France; Department of Neurology (A.M.), Shaare Zedek Medical Center, Jerusalem, Israel; Max-Planck-Institut für terrestrische Mikrobiologie (R.L.), Marburg; and LOEWE Zentrum für Synthetische Mikrobiologie SynMikro (R.L.), Marburg, Germany.
  • 2 From the Department of Neurology and Agnes Ginges Center for Human Neurogenetics (A.L., P.P.), Department of Genetics and Metabolic Diseases (B.-E.Z., M.A., L.C., R.S., I.L., V.M.), Neuro-Ophthalmology Center, Department of Ophthalmology (S.D.), and Department of Radiology (J.M.G.), Hebrew University-Hadassah Medical Center, Jerusalem, Israel; Institut für Zytobiologie und Zytopathologie (C.S., R.L.), Philipps-Universität Marburg, Germany; Laboratoire de Neurogénétique (G.S., M.G.), Ecole Pratique des Hautes Etudes-heSam Universite, Institut du Cerveau et de la Moelle épinière, Paris; Inserm U1127 (G.S., M.G., E.M., A.B.), CNRS UMR7225, Sorbonne Universites, UPMC Univ Paris 06 UMR_1127, Institut du Cerveau et de la Moelle epiniere, ICM, Paris; APHP (G.S., A.B.), Fédération de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris; Institut du Cerveau et de la Moelle épinière (G.S., E.M., A.B.), Genotyping and Sequencing Facility, Paris, France; Department of Neurology (A.M.), Shaare Zedek Medical Center, Jerusalem, Israel; Max-Planck-Institut für terrestrische Mikrobiologie (R.L.), Marburg; and LOEWE Zentrum für Synthetische Mikrobiologie SynMikro (R.L.), Marburg, Germany. vmeiner@hadassah.org.il lill@staff.uni-marburg.de.
PMID: 25609768 DOI: 10.1212/WNL.0000000000001270
Abstract

Objective: To present the clinical, molecular, and cell biological findings in a family with an autosomal recessive form of hereditary spastic paraplegia characterized by a combination of spastic paraplegia, optic atrophy, and peripheral neuropathy (SPOAN).

Methods: We used a combination of whole-genome linkage analysis and exome Sequencing to map the disease locus and to identify the responsible gene. To analyze the physiologic consequences of the disease, we used biochemical and cell biological methods.

Results: Ten members of a highly consanguineous family manifested a childhood-onset SPOAN-like phenotype with slow progression into late adulthood. We mapped this disorder to a locus on chromosome 1q and identified a homozygous donor splice-site mutation in the IBA57 gene, previously implicated in 2 infants with lethal perinatal encephalomyopathy. This gene encodes the mitochondrial iron-sulfur (Fe/S) protein assembly factor IBA57. In addition to a severely decreased amount of normal IBA57 messenger RNA, a patient's cells expressed an aberrantly spliced messenger RNA with a premature stop codon. Lymphoblasts contained 10-fold-lower levels of wild-type, but no signs of truncated IBA57 protein. The decrease in functional IBA57 resulted in reduced levels and activities of several mitochondrial [4Fe-4S] proteins, including complexes I and II, while mitochondrial [2Fe-2S] proteins remained normal.

Conclusions: Our findings reinforce the suggested specific function of IBA57 in mitochondrial [4Fe-4S] protein maturation and provide additional evidence for its role in human disease. The less decreased IBA57 protein level in this family explains phenotypic differences compared with the previously described lethal encephalomyopathy with no functional IBA57.

Figures