Alexander Lossos1, Claudia Stümpfig1, Giovanni Stevanin1, Marion Gaussen1, Bat-El Zimmerman1, Emeline Mundwiller1, Moriya Asulin1, Liat Chamma1, Ruth Sheffer1, Adel Misk1, Shlomo Dotan1, John M Gomori1, Penina Ponger1, Alexis Brice1, Israela Lerer1, Vardiella Meiner2, Roland Lill2. 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.
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.
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.
Authors: Paulo Victor Sgobbi de Souza; Wladimir Bocca Vieira de Rezende Pinto; Gabriel Novaes de Rezende Batistella; Thiago Bortholin; Acary Souza Bulle Oliveira Journal: Cerebellum Date: 2017-04 Impact factor: 3.847
Authors: Benjamin Dennis Weiler; Marie-Christin Brück; Isabell Kothe; Eckhard Bill; Roland Lill; Ulrich Mühlenhoff Journal: Proc Natl Acad Sci U S A Date: 2020-08-12 Impact factor: 11.205