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.
摘要：
α-微管蛋白4A编码基因（TUBA4A）与家族性肌萎缩侧索硬化症（fALS）和额颞叶痴呆（FTD）有关，基于来自不同ALS和FTD队列的患者中可能的致病变异的鉴定。通过筛选由448个不相关的先证者组成的多中心法国队列，这些先证者表现为小脑共济失调，我们确定了超罕见的TUBA4A错义变体，所有这些都不存在于公共数据库中，并且通过多种计算机工具预测了致病性。此外,在100,000基因组项目(100KGP)中进行的基因负荷分析显示,与对照组相比,遗传性共济失调组中TUBA4A罕见变异的富集(OR:57.0847[10.2-576.7];p=4.02x10-07).总之,我们报告了12例表现为痉挛和/或小脑共济失调并具有预测的致病性TUBA4A错义突变的患者，包括5例确诊的从头病例和先前报道的一个出现痉挛性共济失调的大家庭中的突变。来自3例具有明显TUBA4A错觉的患者的培养成纤维细胞显示出微管组织和动力学的显着改变，提供TUBA4A变体致病性的见解。我们的数据证实了具有可变发病年龄的遗传性痉挛性共济失调疾病基因的鉴定，扩大TUBA4A相关表型的临床范围。
