Genetic identification and functional characterisation of novel genes implicated in cerebellar ataxia

遗传性小脑性共济失调是一组影响小脑和其他连接区域的异质性神经生成性疾病。本项目的目的是从基因和功能的角度探索以小脑性共济失调为特征的罕见神经系统疾病。小脑性共济失调，神经病，前庭反射综合征(Canvas)是一种纯特发性迟发性小脑性共济失调，具有包括双侧前庭病变、躯体感觉障碍和小脑损害在内的三重症状。尽管之前有过尝试，但到目前为止，画布还没有遗传基础。该项目在Rfc1内含子区域发现了一个多态的(AAAGG)n扩展重复序列，该重复序列存在于63%的散发性病例中，包括同胞。我们的目的是描述正常筛查队列和迟发性共济失调队列中携带者等位基因频率的频率，估计致病(AAAGG)n以及其他两种多态构象的扩展大小；(AAAAG)n和(AAAGG)n和SNP单倍型筛选所有健康和晚发性共济失调样本，以与患者单倍型进行比较。我们还旨在探索RFC1重复扩增在具有相似临床特征的其他疾病队列中的流行率，包括多系统萎缩(MSA)和非典型帕金森氏症。利用100k基因组计划和英国基因组学(Gel)中包含的丰富数据，并与Illumina和他们的软件Expansion Hunter合作，我们希望开发一种方法来准确检测样本中的Rfc1重复扩展。最后，ACBD5是一种过氧体膜蛋白，是在代谢途径中起关键作用的细胞器。ACBD5此前曾被发现与进行性脑白质营养不良、共济失调和视网膜营养不良的患者有关。来自同一家庭的两名患者患有常染色体隐性共济失调，伴有严重的纯共济失调症状，包括构音障碍、自主运动障碍、眼球运动缓慢和轻度认知障碍。在两名患者中都使用WES发现了ACBD5中的一种隐性无义突变，通过一些全球合作，我们已经确定了其他几个具有该突变的家族。在这个项目中，我们的目标是进行基因分析和功能测试，以阐明这种突变的致病机制。

The inherited cerebellar ataxias are a group of heterogenous, neurogenerative disorders that affect the cerebellum and other connected regions. The aim of this project is to explore rare neurological diseases that feature cerebellar ataxia from a genetic and functional prospective.Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a pure idiopathic late-onset cerebellar ataxia with a triad of symptoms that include bilateral vestibulopathy, somatosensory deficit and cerebellar impairment. So far there is no genetic basis for CANVAS, despite previous attempts. This project identified a polymorphic (AAAGG)n expansion repeat in the intronic region of RFC1 that is present in 63% of sporadic cases tested, including sibships. We aim to characterise the frequency of the carrier allelic frequency in a normal screening cohort and a late-onset ataxia cohort, estimating expansion size of the pathogenic (AAGGG)n as well as two other polymorphic conformations; (AAAAG)n and (AAAGG)n and SNP haplotype screening all healthy and late-onset ataxia samples to compare with patient haplotype. We also aim to explore the prevalence of the RFC1 repeat expansion in other disease cohorts that share similar clinical characteristics including Multiple systems atrophy (MSA) and Atypical Parkinsonism. Capitalising on the wealth of data contained within 100k Genome Project and Genomics England (GEL) and collaborating with Illumina and their software Expansion Hunter, we hope to develop a way to accurately detect the RFC1 repeat expansion in samples. Finally, ACBD5 is a peroxisomal membrane protein which are organelles with key roles in metabolic pathways. ACBD5 has been previously implicated in a patient with progressive leukodystrophy, ataxia and retinal dystrophy. Two patients from the same family suffer from autosomal recessive ataxia with severe pure ataxic symptoms including dysarthria, impaired voluntary movement, slow eye movement and mild cognitive impairment. A recessive nonsense mutation in ACBD5 was found using WES in both patients, and through a number of worldwide collaborations we have identified several other families with this mutation. Within this project, we aim to conduct genetic analysis and functional testing to elucidate the pathogenic mechanism of this mutation.