Year: 2024
Type: article
Study design: Observational Study
Abstract: 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.
Source: Brain
Authors: Mehdi Benkirane, Marion Bonhomme, Heba Morsy, Stephanie L Safgren, Cecilia Marelli, Annabelle Chaussenot, Damian Smedley, Valentina Cipriani, Jean-Madeleine de Sainte-Agathe, Can Ding, Lise Larrieu, Letizia Vestito, Henri Margot, Gaetan Lesca, Francis Ramond, Anna Castrioto, David Baux, Jan Verheijen, Emna Sansa, Paola Giunti, Aline Haetty, Anne Bergougnoux, Morgane Pointaux, Olivier Ardouin, Charles Van Goethem, Marie-Claire Vincent, Marios Hadjivassiliou, Mireille Cossée, Tiphaine Rouaud, Oliver Bartsch, William D Freeman, Klaas J Wierenga, Eric W Klee, Jana Vandrovcova, Henry Houlden, Anne Debant, Michel Koenig
Institutions: Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Physiologie et Médecine Expérimentale du Coeur et des Muscles, Centre Hospitalier Universitaire de Montpellier, Institut Universitaire de Recherche Clinique, Université de Montpellier, Centre de Recherche en Biologie cellulaire de Montpellier, UCL Queen Square Institute of Neurology, University College London, Alexandria University, Mayo Clinic, École Pratique des Hautes Études, Mécanismes moléculaires dans les démences neurodégénératives, Centre Hospitalier Universitaire de Nice, Queen Mary University of London, William Harvey Research Institute, University Medical Center of the Johannes Gutenberg University Mainz, Centre Hospitalier Universitaire de Bordeaux, Lyon 1 Université, Centre Hospitalier Universitaire de Saint-Étienne, Grenoble Institute of Neurosciences, Université Grenoble Alpes, Institute for Neurosciences of Montpellier, University College London Hospitals NHS Foundation Trust, National Hospital for Neurology and Neurosurgery, Sheffield Teaching Hospitals NHS Foundation Trust, Centre Hospitalier Universitaire de Nantes, Mayo Clinic in Florida
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4399758131