De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity
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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 | Vandrovcova, Jana | Houlden, Henry | Debant, Anne | Koenig, Michel | 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 | Walsh, E | Watters, S | Welland, M | Williams, E | Witkowska, K | Wood, S | Zarowiecki, M
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CCSD ; Oxford University Press -
International audience.
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.
