De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.

Autor:	Benkirane M; Laboratoire de Génétique moléculaire, Institut Universitaire de Recherche Clinique, CHU of Montpellier, 34090 Montpellier, France.; Department of Clinical Research, PhyMedExp Univ Montpellier, CNRS UMR 9214, INSERM U1046, 34090 Montpellier, France.; Department of Medical Genetics, Laboratory of Genomics Medicine, Sorbonne University, APHP, 75006 Paris, France., Bonhomme M; Cell Biology Research Department, CRBM (Centre de Recherche en Biologie cellulaire de Montpellier), CNRS, Université de Montpellier, 34293 Montpellier, France., Morsy H; Department of Neuromuscular Diseases, UCL Institute of Neurology, University College London, London WC1N 3BG, UK.; Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt., Safgren SL; Department of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA., Marelli C; MMDN, Université de Montpellier, EPHE, INSERM, Montpellier, France.; Expert center for Neurogenetic Diseases, CHU of Montpellier, 34095 Montpellier, France., Chaussenot A; Department of Medical Genetics, CHU of Nice, 06000 Nice, France., Smedley D; William Harvey Research Institute, Clinical Pharmacology and Precision Medicine, Queen Mary University of London, London EC1M 6BQ, UK., Cipriani V; William Harvey Research Institute, Clinical Pharmacology and Precision Medicine, Queen Mary University of London, London EC1M 6BQ, UK.; UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.; UCL Genetics Institute, University College London, London WC1E 6BT, UK., de Sainte-Agathe JM; Department of Medical Genetics, Laboratory of Genomics Medicine, Sorbonne University, APHP, 75006 Paris, France., Ding C; Institute of human genetics, University of Medicine Mainz, Mainz 55128, Germany., Larrieu L; Laboratoire de Génétique moléculaire, Institut Universitaire de Recherche Clinique, CHU of Montpellier, 34090 Montpellier, France., Vestito L; William Harvey Research Institute, Clinical Pharmacology and Precision Medicine, Queen Mary University of London, London EC1M 6BQ, UK., Margot H; Department of Medical Genetics, CHU of Bordeaux, 33404 Bordeaux, France., Lesca G; Department of Medical Genetics, University Hospitals of Lyon, and Université Claude Bernard Lyon1, 69500 Lyon, France., Ramond F; Department of Medical Genetics, CHU of Saint-Etienne, 42055 Saint-Etienne, France., Castrioto A; Neurology Department, Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, 38706 Grenoble, France., Baux D; Laboratoire de Génétique moléculaire, Institut Universitaire de Recherche Clinique, CHU of Montpellier, 34090 Montpellier, France.; Institut des Neurosciences Montpellier, INM, INSERM, 34000 Montpellier, France.; Montpellier BioInformatics for Clinical Diagnosis (MOBIDIC), Molecular Medicine and Genomics Platform (PMMG), CHU Montpellier, 34295 Montpellier, France., Verheijen J; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA., Sansa E; Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Institute of Neurology, London WC1N 3BG, UK., Giunti P; Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Institute of Neurology, London WC1N 3BG, UK., Haetty A; Institut des Neurosciences Montpellier, INM, INSERM, 34000 Montpellier, France., Bergougnoux A; Laboratoire de Génétique moléculaire, Institut Universitaire de Recherche Clinique, CHU of Montpellier, 34090 Montpellier, France.; Department of Clinical Research, PhyMedExp Univ Montpellier, CNRS UMR 9214, INSERM U1046, 34090 Montpellier, France., Pointaux M; Laboratoire de Génétique moléculaire, Institut Universitaire de Recherche Clinique, CHU of Montpellier, 34090 Montpellier, France., Ardouin O; Laboratoire de Génétique moléculaire, Institut Universitaire de Recherche Clinique, CHU of Montpellier, 34090 Montpellier, France.; Montpellier BioInformatics for Clinical Diagnosis (MOBIDIC), Molecular Medicine and Genomics Platform (PMMG), CHU Montpellier, 34295 Montpellier, France., Van Goethem C; Laboratoire de Génétique moléculaire, Institut Universitaire de Recherche Clinique, CHU of Montpellier, 34090 Montpellier, France.; Montpellier BioInformatics for Clinical Diagnosis (MOBIDIC), Molecular Medicine and Genomics Platform (PMMG), CHU Montpellier, 34295 Montpellier, France., Vincent MC; Laboratoire de Génétique moléculaire, Institut Universitaire de Recherche Clinique, CHU of Montpellier, 34090 Montpellier, France., Hadjivassiliou M; Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2HQ, UK., Cossée M; Laboratoire de Génétique moléculaire, Institut Universitaire de Recherche Clinique, CHU of Montpellier, 34090 Montpellier, France.; Department of Clinical Research, PhyMedExp Univ Montpellier, CNRS UMR 9214, INSERM U1046, 34090 Montpellier, France., Rouaud T; Department of Neurology, CHU of Nantes, 44000 Nantes, France., Bartsch O; Institute of human genetics, University of Medicine Mainz, Mainz 55128, Germany., Freeman WD; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., Wierenga KJ; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA., Klee EW; Department of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA., Vandrovcova J; Department of Neuromuscular Diseases, UCL Institute of Neurology, University College London, London WC1N 3BG, UK., Houlden H; Department of Neuromuscular Diseases, UCL Institute of Neurology, University College London, London WC1N 3BG, UK., Debant A; Cell Biology Research Department, CRBM (Centre de Recherche en Biologie cellulaire de Montpellier), CNRS, Université de Montpellier, 34293 Montpellier, France., Koenig M; Laboratoire de Génétique moléculaire, Institut Universitaire de Recherche Clinique, CHU of Montpellier, 34090 Montpellier, France.; Department of Clinical Research, PhyMedExp Univ Montpellier, CNRS UMR 9214, INSERM U1046, 34090 Montpellier, France.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Nov 04; Vol. 147 (11), pp. 3681-3689.
DOI:	10.1093/brain/awae193
Abstrakt:	Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis and frontotemporal dementia, based on identification of likely pathogenic variants in patients from distinct amyotrophic lateral sclerosis and frontotemporal dementia cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in silico tools. In addition, gene burden analyses in the 100 000 Genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls [odds ratio: 57.0847 (10.2-576.7); P = 4.02 ×10-7]. Taken together, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation, including five confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from three patients harbouring distinct TUBA4A missense showed significant alterations in microtubule organization and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu