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Benkirane, Mehdi; Bonhomme, Marion; Morsy, Heba; Safgren, Stephanie L; Marelli, Cecilia; Chaussenot, Annabelle; Smedley, Damian; Cipriani, Valentina; de Sainte-Agathe, Jean-Madeleine; Ding, Can; Larrieu, Lise; Vestito, Letizia; Margot, Henri; Lesca, Gaetan; Ramond, Francis; Castrioto, Anna; Baux, David; Verheijen, Jan; Sansa, Emna; Giunti, Paola; Haetty, Aline; Bergougnoux, Anne; Pointaux, Morgane; Ardouin, Olivier; [...]

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

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  • Media type: E-Article
  • Title: De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity
  • Contributor: Benkirane, Mehdi; Bonhomme, Marion; Morsy, Heba; Safgren, Stephanie L; Marelli, Cecilia; Chaussenot, Annabelle; Smedley, Damian; Cipriani, Valentina; de Sainte-Agathe, Jean-Madeleine; Ding, Can; Larrieu, Lise; Vestito, Letizia; Margot, Henri; Lesca, Gaetan; Ramond, Francis; Castrioto, Anna; Baux, David; Verheijen, Jan; Sansa, Emna; Giunti, Paola; Haetty, Aline; Bergougnoux, Anne; Pointaux, Morgane; Ardouin, Olivier; [...]
  • Published: Oxford University Press (OUP), 2024
  • Published in: Brain (2024)
  • Language: English
  • DOI: 10.1093/brain/awae193
  • ISSN: 0006-8950; 1460-2156
  • Origination:
  • Footnote:
  • Description: Abstract Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis (fALS) and fronto-temporal dementia (FTD), based on identification of likely pathogenic variants in patients from distinct ALS and FTD 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 (OR: 57.0847 [10.2- 576.7]; p = 4.02 x10-07). Altogether, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harboring a predicted pathogenic TUBA4A missense mutation, including 5 confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from 3 patients harboring distinct TUBA4A missense showed significant alterations in microtubule organisation 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.