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

Authors
Mehdi Benkirane,Marion Bonhomme
Heba Morsy,Stephanie Safgren,Cécilia Marelli,Annabelle Chaussenot,Damian Smedley,Valentina Cipriani,Jean-Madeleine Sainte-Agathe,Can Ding,Lise Larrieu,Letizia Vestito,Henri Margot,Gaëtan Lesca,Francis Ramond,Anna Castrioto,David Baux,Jan Verheijen,Emna Sansa,Paola Giunti,Aline Haetty,Anne Bergougnoux,Morgane Pointaux,Olivier Ardouin,Lucie Guyant‐Maréchal,Marie‐Claire Vincent,Marios Hadjivassiliou,Mireille Cossée,Tiphaine Rouaud,Oliver Bartsch,William Freeman,Klaas Wierenga,Eric Klee,John Ambrose,Janetta Top,Ernest Turro,Marta Bleda,Jenny Taylor,Philip Quirke,C. Boustred,Helen Brittain,Mark Caulfield,Gavin Chan,C.E.H. Craig,Louise Daugherty,Anna Burca,A. Devereau,Greg Elgar,Rebecca Foulger,Tom Fowler,Pedro Furió‐Tarí,J. Hackett,Dina Halai,Angela Hamblin,Shirley Henderson,John Holman,Tim Hubbard,Kristina Ibáñez,Robert Jackson,J. Jones,Dalia Kasperavičiūtė,Melis Kayikci,L. Lahnstein,Katy Lawson,Steven Leigh,Ivone Leong,F. López,F. Maleady-Crowe,Joanne Mason,Ellen McDonagh,Loukas Moutsianas,Michael Mueller,Nirupa Murugaesu,Anna Need,Christopher Odhams,Christine Patch,D. Perez-Gil,Dimitris Polychronopoulos,J. Pullinger,T. Rahim,Augusto Rendon,Pablo Riesgo-Ferreiro,Thomas Rogers,Mina Ryten,K Savage,K. Sawant,Richard Scott,Afshan Siddiq,A. Sieghart,Katherine Smith,Alona Sosinsky,William Spooner,Hallam Stevens,Ashley Stuckey,Răzvan Sultana,Ellen Thomas,Simon Thompson,Carolyn Tregidgo,Arianna Tucci,Edward Walsh,Sarah Watters,M. Welland,Eleanor Williams,Kate Witkowska,S. Wood,Magdalena Zarowiecki,Jana Vandrovcová,Henry Houlden,Anne Debant,M. Kœnig
+108 authors
,J. Ambrose
Journal
Published
Jun 14, 2024
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Abstract

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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