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

遗传性小脑共济失调是一组影响小脑和其他相关区域的异质性神经变性疾病。小脑性共济失调、神经病、前庭反射消失综合征（Cerebellar ataxia，neuropathy，vestibular areflicia syndrome，CANVAS）是一种原发性迟发性小脑性共济失调，具有双侧前庭病变、躯体感觉障碍和小脑损害等三联征。到目前为止，没有遗传基础的帆布，尽管以前的尝试。该项目确定了一个多态性（AAAGG）n扩展重复的内含子区域的RFC 1是目前在63%的散发病例测试，包括同胞。我们的目的是在正常筛查队列和迟发性共济失调队列中检测携带者等位基因频率的频率，估计致病性（AAGGG）n以及其他两种多态性构象的扩展大小;（AAAAG）n和（AAAGG）n和SNP单倍型筛查所有健康和迟发性共济失调样本，以与患者单倍型进行比较。我们还旨在探索RFC 1重复扩展在具有相似临床特征的其他疾病队列中的患病率，包括多系统萎缩（MSA）和非典型帕金森氏症。利用100 k基因组计划和Genomics England（GEL）中包含的丰富数据，并与Illumina及其软件Expansion Hunter合作，我们希望开发一种准确检测样本中RFC 1重复扩增的方法。最后，ACBD 5是过氧化物酶体膜蛋白，其是在代谢途径中具有关键作用的细胞器。ACBD 5先前已经涉及患有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。来自同一家族的两名患者患有常染色体隐性遗传性共济失调，具有严重的纯共济失调症状，包括构音障碍、自主运动受损、眼球运动缓慢和轻度认知障碍。使用WES在这两名患者中发现了ACBD 5的隐性无义突变，并且通过一些全球合作，我们已经确定了其他几个具有这种突变的家庭。在这个项目中，我们的目标是进行遗传分析和功能测试，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.