在罕见病中，脊髓小脑共济失调（SCA）是对于人群影响较大的一类疾病，具有高度遗传异质性和临床变异性，均为严重致残性疾病，迄今缺乏针对性治疗方法。中国的SCA3约占SCA的50%-60%，与另外6种SCA疾病和亨廷顿舞蹈病同属多聚谷氨酰胺疾病，基因编码区CAG重复序列不稳定性导致动态突变，而扩展重复次数仅能解释部分临床变异。我们团队20年来致力于遗传性共济失调的临床和基因分析，积累了大量SCA家系资源。本课题将与清华大学生物信息分析团队合作，基于家系进行全基因组测序分析，重点关注DNA代谢活性各环节、polyQ病发病机制相关及ataxin3相互作用蛋白；三代测序构建ATXN3基因及其上游序列单体型；研究其它polyQ疾病重复序列对于SCA3表型的影响。通过对顺式作用元件和反式作用因子的分析，研究SCA3动态突变过程和临床变异相关遗传调节因素，对于探索发病机制和针对性治疗靶点具有重要科学意义。

Spinocerebellar ataxia (SCA) is a group of devastating rare diseases currently with very limited therapeutic options. SCA has high genotypic and phenotypic heterogeneity, and a few causal genes have been identified thus far. About 50-60% of all SCAs in Chinese population are SCA type 3 (SCA3) attributed to the ATXN3 gene mutations. Similar to Huntington’s disease, SCA3 and additional 6 types of SCAs are due to CAG triplet repeat mutations in their causal genes which lead to the large number of repeats of glutamine residues (PolyQ) in the disease-associated proteins. While the severity of these SCAs is in general correlated with the length of the expanded CAG alleles, but a considerable amount of phenotypic variability in these diseases are not able to be explained by the number of CAGs, suggesting modifying factors may also be involved. Over the past 20 years, our team has been focusing on both clinical and genetic research on SCAs, with a number of SCA pedigrees collected and a standard SCA diagnostic pipeline established. In this application, we aim to collaborate with the bioinformatics groups of Tsinghua University, to perform a genome-wide sequencing analysis in multiple SCA pedigrees. In particular, we will concentrate on the DNA metabolism pathway,polyQ-related genes and ataxin3 interacting proteins. More specifically, ATXN3 gene and its upstream sequence will be sequenced using the third generation sequencing technology. At the same time, we will check CAG repeats of other polyQ disease causal genes to identify the influences on the age of onset of SCA3. Through detailed delineating of both cis-and trans-regulatory elements, we expect that our study will identify key modifiers involved in SCA pathogenesis, which would further reveal the mechanism underlying the linkage between dynamic mutations and phenotypic variability, thus fostering potentially novel therapeutic strategies.

中国的SCA3约占SCA的50%-60%，与另外6种SCA疾病和亨廷顿舞蹈病同属多聚谷氨酰胺疾病，基因编码区CAG重复序列不稳定性导致动态突变。我们团队20年来致力于遗传性共济失调的临床和基因分析，积累了大量SCA家系资源。本课题基于三代测序构建ATXN3基因及其上游序列单体型，通过对顺式作用元件的分析，研究SCA3动态突变机制。