Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia.
Neurology. 2015-01-21; 84(7): 659-667
DOI: 10.1212/WNL.0000000000001270
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1. Neurology. 2015 Feb 17;84(7):659-67. doi: 10.1212/WNL.0000000000001270. Epub 2015
Jan 21.
Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia.
Lossos A(1), Stümpfig C(1), Stevanin G(1), Gaussen M(1), Zimmerman BE(1),
Mundwiller E(1), Asulin M(1), Chamma L(1), Sheffer R(1), Misk A(1), Dotan S(1),
Gomori JM(1), Ponger P(1), Brice A(1), Lerer I(1), Meiner V(2), Lill R(2).
Author information:
(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.
.
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.
© 2015 American Academy of Neurology.
DOI: 10.1212/WNL.0000000000001270
PMID: 25609768 [Indexed for MEDLINE]