De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity
Résumé
Abstract Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis and frontotemporal dementia, based on identification of likely pathogenic variants in patients from distinct amyotrophic lateral sclerosis and frontotemporal dementia 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 [odds ratio: 57.0847 (10.2−576.7); P = 4.02 ×10−7]. Taken together, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation, including five confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from three patients harbouring distinct TUBA4A missense showed significant alterations in microtubule organization 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.
Mots clés
cause spastic ataxia TUBA4A monoallelic variants cause spastic ataxia Ataxia TUBA4A Spasticity
De novo Tubulinopathy
Cerebellar atrophy Amyotrophic Lateral Sclerosis CCAS: Cerebellar Cognitive and Affective Syndrome FTD: Fronto-Temporal Dementia. HA: Hereditary Ataxia HSP: Hereditary Spastic Paraplegia LMN: Lower motor neuron MAP: Microtubule Associated Protein MT: Microtubules MSP: Multiple Systemic Proteinopathy PTM: Post-Translational Modifications PLS: Primary Lateral Sclerosis UMN: Upper motor neuron
cause spastic ataxia TUBA4A monoallelic variants cause spastic ataxia Ataxia
TUBA4A
Spasticity
De novo
Tubulinopathy
Cerebellar atrophy Amyotrophic Lateral Sclerosis
CCAS: Cerebellar Cognitive and Affective Syndrome
FTD: Fronto-Temporal Dementia. HA: Hereditary Ataxia
HSP: Hereditary Spastic Paraplegia
LMN: Lower motor neuron
MAP: Microtubule Associated Protein
MT: Microtubules
MSP: Multiple Systemic Proteinopathy
PTM: Post-Translational Modifications
PLS: Primary Lateral Sclerosis
UMN: Upper motor neuron
Domaines
Sciences du Vivant [q-bio]| Origine | Fichiers produits par l'(les) auteur(s) |
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Domaine public
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