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

Mehdi Benkirane; Marion Bonhomme; Heba Morsy; Stephanie Safgren; Cecilia Marelli; Annabelle Chaussenot; Damian Smedley; Valentina Cipriani; Jean-Madeleine de Sainte-Agathe; Can Ding; Lise Larrieu; Letizia Vestito; Henri Margot; Gaetan Lesca; Francis Ramond; Anna Castrioto; David Baux; Jan Verheijen; Emna Sansa; Paola Giunti; Aline Haetty; Anne Bergougnoux; Morgane Pointaux; Olivier Ardouin; Charles van Goethem; Marie-Claire Vincent; Marios Hadjivassiliou; Mireille Cossée; Tiphaine Rouaud; Oliver Bartsch; William Freeman; Klaas Wierenga; Eric Klee; Jana Vandrovcova; Henry Houlden; Anne Debant; Michel Koenig; J Ambrose; P Arumugam; E Baple; M Bleda; F Boardman-Pretty; J Boissiere; C Boustred; H Brittain; M Caulfield; G Chan; C Craig; L Daugherty; A de Burca; A Devereau; G Elgar; R Foulger; T Fowler; P Furió-Tarí; J Hackett; D Halai; A Hamblin; S Henderson; J Holman; T Hubbard; K Ibáñez; R Jackson; L Jones; D Kasperaviciute; M Kayikci; L Lahnstein; K Lawson; S Leigh; I Leong; F Lopez; F Maleady-Crowe; J Mason; E Mcdonagh; L Moutsianas; M Mueller; N Murugaesu; A Need; C Odhams; C Patch; D Perez-Gil; D Polychronopoulos; J Pullinger; T Rahim; A Rendon; P Riesgo-Ferreiro; T Rogers; M Ryten; K Savage; K Sawant; R Scott; A Siddiq; A Sieghart; D Smedley; K Smith; A Sosinsky; W Spooner; H Stevens; A Stuckey; R Sultana; E Thomas; S Thompson; C Tregidgo; A Tucci; E Walsh; S Watters; M Welland; E Williams; K Witkowska; S Wood; M Zarowiecki

doi:10.1093/brain/awae193

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

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

Mehdi Benkirane, Marion Bonhomme, Heba Morsy, Stephanie Safgren, Cecilia Marelli, Annabelle Chaussenot, Damian Smedley, Valentina Cipriani, Jean-Madeleine de Sainte-Agathe, Can Ding, …

Brain - A Journal of Neurology , Vol.147(11)

11/2024

DOI: https://doi.org/10.1093/brain/awae193

PMID: 38884572

Abstract

ataxia

TUBA4A

spasticity

de novo

tubulinopathy

cerebellar atrophy

ataxia

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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Title: De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity
Creators - without role: Mehdi Benkirane - Université de Montpellier, Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Marion Bonhomme - Université de Montpellier, Centre de Recherche en Biologie Cellulaire de Montpellier - CRBM
Heba Morsy - University College London
Stephanie Safgren - Mayo Clinic in Florida
Cecilia Marelli - Université de Montpellier, Mécanismes Moléculaires dans les Démences Neurodégénératives - MMDN
Annabelle Chaussenot - Dpt génétique médicale [CHU Nice]
Damian Smedley - William Harvey Research Institute
Valentina Cipriani - William Harvey Research Institute
Jean-Madeleine de Sainte-Agathe - Sorbonne Université
Can Ding
Lise Larrieu - Institut Universitaire de Recherche Clinique
Letizia Vestito - William Harvey Research Institute
Henri Margot - Centre Hospitalier Universitaire de Bordeaux
Gaetan Lesca - Lyon College
Francis Ramond - Centre Hospitalier Universitaire de Saint-Étienne
Anna Castrioto - Université Grenoble Alpes
David Baux - Institut Universitaire de Recherche Clinique
Jan Verheijen - Mayo Clinic
Emna Sansa - National Hospital for Neurology and Neurosurgery
Paola Giunti - University College London Hospitals NHS Foundation Trust
Aline Haetty - Université de Montpellier, Institut des Neurosciences de Montpellier - INM
Anne Bergougnoux - Université de Montpellier, Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Morgane Pointaux - Institut Universitaire de Recherche Clinique
Olivier Ardouin - Institut Universitaire de Recherche Clinique
Charles van Goethem - Institut Universitaire de Recherche Clinique
Marie-Claire Vincent - Institut Universitaire de Recherche Clinique
Marios Hadjivassiliou - Sheffield Teaching Hospitals NHS Foundation Trust
Mireille Cossée - Université de Montpellier, Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Tiphaine Rouaud - Centre Hospitalier Universitaire de Nantes
Oliver Bartsch
William Freeman - Mayo Clinic in Florida
Klaas Wierenga - Mayo Clinic in Florida
Eric Klee - Mayo Clinic in Florida
Jana Vandrovcova - University College London
Henry Houlden - University College London
Anne Debant - Université de Montpellier, Centre de Recherche en Biologie Cellulaire de Montpellier - CRBM
Michel Koenig - Institut Universitaire de Recherche Clinique
J Ambrose
P Arumugam
E Baple
M Bleda
F Boardman-Pretty
J Boissiere
C Boustred
H Brittain
M Caulfield
G Chan
C Craig
L Daugherty
A de Burca
A Devereau
G Elgar
R Foulger
T Fowler
P Furió-Tarí
J Hackett
D Halai
A Hamblin
S Henderson
J Holman
T Hubbard
K Ibáñez
R Jackson
L Jones
D Kasperaviciute
M Kayikci
L Lahnstein
K Lawson
S Leigh
I Leong
F Lopez
F Maleady-Crowe
J Mason
E Mcdonagh
L Moutsianas
M Mueller
N Murugaesu
A Need
C Odhams
C Patch
D Perez-Gil
D Polychronopoulos
J Pullinger
T Rahim
A Rendon
P Riesgo-Ferreiro
T Rogers
M Ryten
K Savage
K Sawant
R Scott
A Siddiq
A Sieghart
D Smedley - William Harvey Research Institute
K Smith
A Sosinsky
W Spooner
H Stevens
A Stuckey
R Sultana
E Thomas
S Thompson
C Tregidgo
A Tucci
E Walsh
S Watters
M Welland
E Williams
K Witkowska
S Wood
M Zarowiecki
Publication Details: Brain - A Journal of Neurology , Vol.147(11)
Grant note: 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
Identifiers: 9933962909311
Academic Unit: Institut des Neurosciences de Montpellier - INM; Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp; Centre de Recherche en Biologie Cellulaire de Montpellier - CRBM; Mécanismes Moléculaires dans les Démences Neurodégénératives - MMDN
Language: English
Resource Type: Journal article
Local Fields: hal-04615151