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)
1
PhyMedExp -
Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
2 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
3 CHU Pitié-Salpêtrière [AP-HP]
4 CRBM - Centre de recherche en Biologie cellulaire de Montpellier
5 MMDN - Mécanismes moléculaires dans les démences neurodégénératives
6 Dpt génétique médicale [CHU Nice]
7 IURC Montpellier - Institut Universitaire de Recherche Clinique
8 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
9 CIC CHU Lyon (inserm)
10 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
11 GIN - [GIN] Grenoble Institut des Neurosciences
12 CHU Montpellier = Montpellier University Hospital
13 INM - Institut des Neurosciences de Montpellier
14 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
2 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
3 CHU Pitié-Salpêtrière [AP-HP]
4 CRBM - Centre de recherche en Biologie cellulaire de Montpellier
5 MMDN - Mécanismes moléculaires dans les démences neurodégénératives
6 Dpt génétique médicale [CHU Nice]
7 IURC Montpellier - Institut Universitaire de Recherche Clinique
8 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
9 CIC CHU Lyon (inserm)
10 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
11 GIN - [GIN] Grenoble Institut des Neurosciences
12 CHU Montpellier = Montpellier University Hospital
13 INM - Institut des Neurosciences de Montpellier
14 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
Mehdi Benkirane
- Function : Author
- PersonId : 1155947
- ORCID : 0000-0001-6445-6347
Heba Morsy
- Function : Author
- PersonId : 1182349
- ORCID : 0000-0002-9047-0959
Stephanie Safgren
- Function : Author
Damian Smedley
- Function : Author
- PersonId : 1393061
- ORCID : 0000-0002-5836-9850
Valentina Cipriani
- Function : Author
Can Ding
- Function : Author
Letizia Vestito
- Function : Author
Gaetan Lesca
- Function : Author
- PersonId : 769268
- ORCID : 0000-0001-7691-9492
- IdRef : 124685811
David Baux
- Function : Author
- PersonId : 181520
- IdHAL : david-baux
- ORCID : 0000-0003-3423-1221
- IdRef : 144791056
Jan Verheijen
- Function : Author
Emna Sansa
- Function : Author
Paola Giunti
- Function : Author
Marios Hadjivassiliou
- Function : Author
Oliver Bartsch
- Function : Author
William Freeman
- Function : Author
- PersonId : 1393062
- ORCID : 0000-0003-2326-0633
Klaas Wierenga
- Function : Author
Eric Klee
- Function : Author
- PersonId : 1393063
- ORCID : 0000-0003-2946-5795
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
- Function : Author
- PersonId : 1393064
- ORCID : 0000-0001-9508-0477
Henry Houlden
- Function : Author
- PersonId : 763785
- ORCID : 0000-0002-2866-7777
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.
Domains
Life Sciences [q-bio]
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2024 Benkirane et al., De novo and inherited.pdf (950.04 Ko)
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