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

小脑共济失调新基因的遗传鉴定和功能表征

基本信息

批准号：
1936823
负责人：
金额：
--
依托单位：
University College London
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1936823
关键词：
Genetic identification functional characterisation novel

项目摘要

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.

遗传性小脑共济失调是一组影响小脑和其他连接区域的异质神经生成性疾病。该项目的目的是从遗传和功能角度探讨以小脑共济失调为特征的罕见神经系统疾病。小脑共济失调、神经病、前庭无反射综合征 (CANVAS) 是一种纯特发性迟发性小脑共济失调，具有三联征，包括双侧前庭疾病、体感缺陷和小脑损伤。尽管之前有过尝试，但迄今为止 CANVAS 还没有遗传基础。该项目在 RFC1 的内含子区域中发现了多态性 (AAAGG)n 扩展重复，该重复存在于 63% 的测试散发病例（包括同胞）中。我们的目的是表征正常筛查队列和晚发性共济失调队列中携带者等位基因频率的特征，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 以及 SNP 单倍型筛选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 RFC1 重复扩增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) 和非典型帕金森病。利用 100k 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，我们希望开发出一种准确检测样本中 RFC1 重复扩增的方法。最后，ACBD5 是一种过氧化物酶体膜蛋白，是在代谢途径中发挥关键作用的细胞器。 ACBD5 此前已被证实与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有关。来自同一家族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、随意运动受损、眼球运动缓慢和轻度认知障碍。使用 WES 在两名患者中发现了 ACBD5 的隐性无义突变，并且通过一系列全球合作，我们已经确定了其他几个具有这种突变的家族。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。