Benkirane, Mehdi;
Bonhomme, Marion;
Morsy, Heba;
Safgren, Stephanie L;
Marelli, Cecilia;
Chaussenot, Annabelle;
Smedley, Damian;
... Koenig, Michel; + view all
(2024)
De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.
Brain
, Article awae193. 10.1093/brain/awae193.
(In press).
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awae193.pdf - Accepted Version Access restricted to UCL open access staff until 18 June 2025. Download (1MB) |
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.
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