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

• Published in: Brain (London, England : 1878) England : 1878), 2024-06
• Main Authors: Benkirane, Mehdi, Bonhomme, Marion, Morsy, Heba, Safgren, Stephanie, 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, van Goethem, Charles, Vincent, Marie-Claire, Hadjivassiliou, Marios, Cossée, Mireille, Rouaud, Tiphaine, Bartsch, Oliver, Freeman, William, Wierenga, Klaas, Klee, Eric, Ambrose, J, Arumugam, P, Baple, E, Bleda, M, Boardman-Pretty, F, Boissiere, J, Boustred, C, Brittain, H, Caulfield, M, Chan, G, Craig, C, Daugherty, L, de Burca, A, Devereau, A, Elgar, G, Foulger, R, Fowler, T, Furió-Tarí, P, Hackett, J, Halai, D, Hamblin, A, Henderson, S, Holman, J, Hubbard, T, Ibáñez, K, Jackson, R, Jones, L, Kasperaviciute, D, Kayikci, M, Lahnstein, L, Lawson, K, Leigh, S, Leong, I, Lopez, F, Maleady-Crowe, F, Mason, J, Mcdonagh, E, Moutsianas, L, Mueller, M, Murugaesu, N, Need, A, Odhams, C, Patch, C, Perez-Gil, D, Polychronopoulos, D, Pullinger, J, Rahim, T, Rendon, A, Riesgo-Ferreiro, P, Rogers, T, Ryten, M, Savage, K, Sawant, K, Scott, R, Siddiq, A, Sieghart, A, Smedley, D, Smith, K, Sosinsky, A, Spooner, W, Stevens, H, Stuckey, A, Sultana, R, Thomas, E, Thompson, S, Tregidgo, C, Tucci, A
• Format: Article
• Language: English
• Subjects: Life Sciences
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awae193

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.