De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity - Université de Lyon
Journal Articles Brain - A Journal of Neurology Year : 2024

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

Mehdi Benkirane (1, 2, 3) , Marion Bonhomme (4) , Heba Morsy , Stephanie Safgren , Cecilia Marelli (5) , Annabelle Chaussenot (6) , Damian Smedley , Valentina Cipriani , Jean-Madeleine de Sainte-Agathe (3) , Can Ding , Lise Larrieu (7) , Letizia Vestito , Henri Margot (8) , Gaetan Lesca (9) , Francis Ramond (10) , Anna Castrioto (11) , David Baux (7, 12, 13) , Jan Verheijen , Emna Sansa , Paola Giunti , Aline Haetty (13) , Anne Bergougnoux (1, 2) , Morgane Pointaux (7, 12) , Olivier Ardouin (7, 12) , Charles van Goethem (7, 12) , Marie-Claire Vincent (7, 12) , Marios Hadjivassiliou , Mireille Cossée (1, 2) , Tiphaine Rouaud (14) , Oliver Bartsch , William Freeman , Klaas Wierenga , Eric Klee , 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 , Jana Vandrovcova , Henry Houlden , Anne Debant (4) , Michel Koenig (1, 2)
Heba Morsy
Stephanie Safgren
  • Function : Author
Damian Smedley
Valentina Cipriani
  • Function : Author
Can Ding
  • Function : Author
Letizia Vestito
  • Function : Author
Gaetan Lesca
Jan Verheijen
  • Function : Author
Emna Sansa
  • Function : Author
Paola Giunti
  • Function : Author
Marios Hadjivassiliou
  • Function : Author
Oliver Bartsch
  • Function : Author
William Freeman
Klaas Wierenga
  • Function : Author
Eric Klee
J Ambrose
  • Function : Author
P Arumugam
  • Function : Author
E Baple
  • Function : Author
M Bleda
  • Function : Author
F Boardman-Pretty
  • Function : Author
J Boissiere
  • Function : Author
C Boustred
  • Function : Author
H Brittain
  • Function : Author
M Caulfield
  • Function : Author
G Chan
  • Function : Author
C Craig
  • Function : Author
L Daugherty
  • Function : Author
A de Burca
  • Function : Author
A Devereau
  • Function : Author
G Elgar
  • Function : Author
R Foulger
  • Function : Author
T Fowler
  • Function : Author
P Furió-Tarí
  • Function : Author
J Hackett
  • Function : Author
D Halai
  • Function : Author
A Hamblin
  • Function : Author
S Henderson
  • Function : Author
J Holman
  • Function : Author
T Hubbard
  • Function : Author
K Ibáñez
  • Function : Author
R Jackson
  • Function : Author
L Jones
  • Function : Author
D Kasperaviciute
  • Function : Author
M Kayikci
  • Function : Author
L Lahnstein
  • Function : Author
K Lawson
  • Function : Author
S Leigh
  • Function : Author
I Leong
  • Function : Author
F Lopez
  • Function : Author
F Maleady-Crowe
  • Function : Author
J Mason
  • Function : Author
E Mcdonagh
  • Function : Author
L Moutsianas
  • Function : Author
M Mueller
  • Function : Author
N Murugaesu
  • Function : Author
A Need
  • Function : Author
C Odhams
  • Function : Author
C Patch
  • Function : Author
D Perez-Gil
  • Function : Author
D Polychronopoulos
  • Function : Author
J Pullinger
  • Function : Author
T Rahim
  • Function : Author
A Rendon
  • Function : Author
P Riesgo-Ferreiro
  • Function : Author
T Rogers
  • Function : Author
M Ryten
  • Function : Author
K Savage
  • Function : Author
K Sawant
  • Function : Author
R Scott
  • Function : Author
A Siddiq
  • Function : Author
A Sieghart
  • Function : Author
D Smedley
  • Function : Author
K Smith
  • Function : Author
A Sosinsky
  • Function : Author
W Spooner
  • Function : Author
H Stevens
  • Function : Author
A Stuckey
  • Function : Author
R Sultana
  • Function : Author
E Thomas
  • Function : Author
S Thompson
  • Function : Author
C Tregidgo
  • Function : Author
A Tucci
  • Function : Author
E Walsh
  • Function : Author
S Watters
  • Function : Author
M Welland
  • Function : Author
E Williams
  • Function : Author
K Witkowska
  • Function : Author
S Wood
  • Function : Author
M Zarowiecki
  • Function : Author
Jana Vandrovcova
Henry Houlden

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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Dates and versions

hal-04615151 , version 1 (27-12-2024)

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Mehdi Benkirane, Marion Bonhomme, Heba Morsy, Stephanie Safgren, Cecilia Marelli, et al.. De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity. Brain - A Journal of Neurology , 2024, ⟨10.1093/brain/awae193⟩. ⟨hal-04615151⟩
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