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

Mehdi Benkirane^{1

2

3}, Marion Bonhomme⁴, Heba Morsy^{5

6}, Stephanie L Safgren⁷, Cecilia Marelli⁸, Annabelle Chaussenot⁹, Damian Smedley¹⁰, Valentina Cipriani^{10

11

12}, Jean-Madeleine de Sainte-Agathe³, Can Ding¹³, Lise Larrieu¹, Letizia Vestito¹⁰, Henri Margot¹⁴, Gaetan Lesca¹⁵, Francis Ramond¹⁶, Anna Castrioto¹⁷, David Baux^{1

18

19}, Jan Verheijen²⁰, Emna Sansa²¹, Paola Giunti²¹, Aline Haetty¹⁸, Anne Bergougnoux^{1

2}, Morgane Pointaux¹, Olivier Ardouin^{1

19}, Charles Van Goethem^{1

19}, Marie-Claire Vincent¹, Marios Hadjivassiliou²², Mireille Cossée^{1

2}, Tiphaine Rouaud²³, Oliver Bartsch¹³, William D Freeman²⁴, Klaas J Wierenga²⁵, Eric W Klee^{7

26

27}; Genomic England Research Consortium; Jana Vandrovcova⁵, Henry Houlden⁵, Anne Debant⁴, Michel Koenig^{1

2}

Collaborators, Affiliations

Collaborators

Genomic England Research Consortium:
J C Ambrose, P Arumugam, E L Baple, M Bleda, F Boardman-Pretty, J M Boissiere, C R Boustred, H Brittain, M J Caulfield, G C Chan, C E H Craig, L C Daugherty, A de Burca, A Devereau, G Elgar, R E Foulger, T Fowler, P Furió-Tarí, J M Hackett, D Halai, A Hamblin, S Henderson, J E Holman, T J P Hubbard, K Ibáñez, R Jackson, L J Jones, D Kasperaviciute, M Kayikci, L Lahnstein, K Lawson, S E A Leigh, I U S Leong, F J Lopez, F Maleady-Crowe, J Mason, E M McDonagh, L Moutsianas, M Mueller, N Murugaesu, A C Need, C A 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 H Scott, A Siddiq, A Sieghart, D Smedley, K R Smith, A Sosinsky, W Spooner, H E Stevens, A Stuckey, R Sultana, E R A Thomas, S R Thompson, C Tregidgo, A Tucci, E Walsh, S A Watters, M J Welland, E Williams, K Witkowska, S M Wood, M Zarowiecki

Affiliations

¹ Laboratoire de Génétique moléculaire, Institut Universitaire de Recherche Clinique, CHU of Montpellier, 34090 Montpellier, France.
² PhyMedExp Univ Montpellier, CNRS UMR 9214, INSERM U1046, 34090 Montpellier, France.
³ Department of Medical Genetics, Laboratory of Genomics Medicine, Sorbonne University, APHP, 75006 Paris, France.
⁴ CRBM (Centre de Recherche en Biologie cellulaire de Montpellier), CNRS, Université de Montpellier, 34293 Montpellier, France.
⁵ Department of Neuromuscular Diseases, UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
⁶ Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt.
⁷ Department of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
⁸ MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France; Expert center for Neurogenetic Diseases, CHU of Montpellier, 34095 Montpellier, France.
⁹ Department of Medical Genetics, CHU of Nice, 06000 Nice, France.
¹⁰ William Harvey Research Institute, Clinical Pharmacology and Precision Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
¹¹ UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
¹² UCL Genetics Institute, University College London, London WC1E 6BT, UK.
¹³ Institute of human genetics, University of Medicine Mainz, Mainz 55128, Germany.
¹⁴ Department of Medical Genetics, CHU of Bordeaux, 33404 Bordeaux, France.
¹⁵ Department of Medical Genetics, University Hospitals of Lyon, and Université Claude Bernard Lyon1, 69500 Lyon, France.
¹⁶ Department of Medical Genetics, CHU of Saint-Etienne, 42055 Saint-Etienne, France.
¹⁷ Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Neurology Department, 38706 Grenoble, France.
¹⁸ INM, Institut des Neurosciences Montpellier, INSERM, 34000 Montpellier, France.
¹⁹ Montpellier BioInformatics for Clinical Diagnosis (MOBIDIC), Molecular Medicine and Genomics Platform (PMMG), CHU Montpellier, 34295 Montpellier, France.
²⁰ Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
²¹ Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Institute of Neurology, London WC1N 3BG, UK.
²² Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2HQ, UK.
²³ Department of Neurology, CHU of Nantes, 44000 Nantes, France.
²⁴ Department of Neurology, Mayo Clinic Jacksonville, FL 32224, USA.
²⁵ Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA.
²⁶ Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
²⁷ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA.

PMID: 38884572
DOI: 10.1093/brain/awae193

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

Mehdi Benkirane et al. Brain. 2024.

. 2024 Jun 17:awae193.

doi: 10.1093/brain/awae193. Online ahead of print.

Authors

Collaborators

Genomic England Research Consortium:
J C Ambrose, P Arumugam, E L Baple, M Bleda, F Boardman-Pretty, J M Boissiere, C R Boustred, H Brittain, M J Caulfield, G C Chan, C E H Craig, L C Daugherty, A de Burca, A Devereau, G Elgar, R E Foulger, T Fowler, P Furió-Tarí, J M Hackett, D Halai, A Hamblin, S Henderson, J E Holman, T J P Hubbard, K Ibáñez, R Jackson, L J Jones, D Kasperaviciute, M Kayikci, L Lahnstein, K Lawson, S E A Leigh, I U S Leong, F J Lopez, F Maleady-Crowe, J Mason, E M McDonagh, L Moutsianas, M Mueller, N Murugaesu, A C Need, C A 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 H Scott, A Siddiq, A Sieghart, D Smedley, K R Smith, A Sosinsky, W Spooner, H E Stevens, A Stuckey, R Sultana, E R A Thomas, S R Thompson, C Tregidgo, A Tucci, E Walsh, S A Watters, M J Welland, E Williams, K Witkowska, S M Wood, M Zarowiecki

Affiliations

¹ Laboratoire de Génétique moléculaire, Institut Universitaire de Recherche Clinique, CHU of Montpellier, 34090 Montpellier, France.
² PhyMedExp Univ Montpellier, CNRS UMR 9214, INSERM U1046, 34090 Montpellier, France.
³ Department of Medical Genetics, Laboratory of Genomics Medicine, Sorbonne University, APHP, 75006 Paris, France.
⁴ CRBM (Centre de Recherche en Biologie cellulaire de Montpellier), CNRS, Université de Montpellier, 34293 Montpellier, France.
⁵ Department of Neuromuscular Diseases, UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
⁶ Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt.
⁷ Department of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
⁸ MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France; Expert center for Neurogenetic Diseases, CHU of Montpellier, 34095 Montpellier, France.
⁹ Department of Medical Genetics, CHU of Nice, 06000 Nice, France.
¹⁰ William Harvey Research Institute, Clinical Pharmacology and Precision Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
¹¹ UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
¹² UCL Genetics Institute, University College London, London WC1E 6BT, UK.
¹³ Institute of human genetics, University of Medicine Mainz, Mainz 55128, Germany.
¹⁴ Department of Medical Genetics, CHU of Bordeaux, 33404 Bordeaux, France.
¹⁵ Department of Medical Genetics, University Hospitals of Lyon, and Université Claude Bernard Lyon1, 69500 Lyon, France.
¹⁶ Department of Medical Genetics, CHU of Saint-Etienne, 42055 Saint-Etienne, France.
¹⁷ Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Neurology Department, 38706 Grenoble, France.
¹⁸ INM, Institut des Neurosciences Montpellier, INSERM, 34000 Montpellier, France.
¹⁹ Montpellier BioInformatics for Clinical Diagnosis (MOBIDIC), Molecular Medicine and Genomics Platform (PMMG), CHU Montpellier, 34295 Montpellier, France.
²⁰ Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
²¹ Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Institute of Neurology, London WC1N 3BG, UK.
²² Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2HQ, UK.
²³ Department of Neurology, CHU of Nantes, 44000 Nantes, France.
²⁴ Department of Neurology, Mayo Clinic Jacksonville, FL 32224, USA.
²⁵ Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA.
²⁶ Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
²⁷ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA.

PMID: 38884572
DOI: 10.1093/brain/awae193

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.

Keywords: TUBA4A; ataxia; cerebellar atrophy; de novo; spasticity; tubulinopathy.

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

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