| Title: |
De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity |
| 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; 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 |
| Contributors: |
Physiologie & médecine expérimentale du Cœur et des Muscles U 1046 (PhyMedExp); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM); Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier); CHU Pitié-Salpêtrière AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); Centre de recherche en Biologie cellulaire de Montpellier (CRBM); Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM); University College London UCL (UCL); Alexandria University Alexandrie; Mayo Clinic Rochester; Mécanismes moléculaires dans les démences neurodégénératives (MMDN); École Pratique des Hautes Études (EPHE); Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM); Dpt génétique médicale CHU Nice; Centre Hospitalier Universitaire de Nice (CHU Nice); Queen Mary University of London (QMUL); Institut Universitaire de Recherche Clinique (IURC Montpellier); Centre Hospitalier Universitaire de Bordeaux (CHU Bordeaux); CIC CHU Lyon (inserm); Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM); Centre Hospitalier Universitaire de Saint-Etienne CHU Saint-Etienne (CHU ST-E); GIN Grenoble Institut des Neurosciences (GIN); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA); CHU Montpellier = Montpellier University Hospital; Institut des Neurosciences de Montpellier (INM); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM); University College London Hospitals (UCLH); Centre Hospitalier Universitaire de Nantes = Nantes University Hospital (CHU Nantes); M.K. is in part supported by the patients’ association ‘Connaître les Syndromes Cérébelleux’ (CSC). The 100 000 Genomes Project is funded by the National Institute for Health and Care Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded the research infrastructure |
| Source: |
ISSN: 0006-8950. |
| Publisher Information: |
CCSD; Oxford University Press |
| Publication Year: |
2024 |
| Collection: |
Université de Montpellier: HAL |
| Subject Terms: |
ataxia; TUBA4A; spasticity; de novo; tubulinopathy; cerebellar atrophy; [SDV]Life Sciences [q-bio] |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/38884572; PUBMED: 38884572 |
| DOI: |
10.1093/brain/awae193 |
| Availability: |
https://hal.science/hal-04615151; https://hal.science/hal-04615151v1/document; https://hal.science/hal-04615151v1/file/2024%20Benkirane%20et%20al.,%20De%20novo%20and%20inherited.pdf; https://doi.org/10.1093/brain/awae193 |
| Rights: |
https://about.hal.science/hal-authorisation-v1/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.836F2D8E |
| Database: |
BASE |