Spinocerebellar Ataxia Type 10

描述(摘自申请者摘要)：脊髓小脑性共济失调10型 (SCA 10)是一种常染色体显性遗传病，以小脑性共济失调为特征， 癫痫发作和期待。SCA1O突变是一个巨大的(4-22kb)的扩展 未知新基因E46内含子9的ATTCT五核苷酸重复序列 功能，位于染色体22q13.3上。这个项目的长期目标是 阐明SCA1 0的分子机制，开发合理的治疗方法 基于这种进行性疾病的致病机制的策略 使人衰弱的疾病。这个应用程序将调查 扩增的ATTCT重复导致疾病表型。的假说 拟议的项目是ATTCT重复序列的扩大通过以下方式导致疾病 通过重复大小依赖的机制改变E46转录本。SCA1%0 是一种新发现的显性遗传性共济失调，其 流行病学、临床和遗传学特征尚未完全 特色化的。因此，进一步表征基因、表型和 SCA10患者的基因-表型相关性需要作为起点 ，并被指定为具体目标1.实现这一目标 明确的目标应该会加强我们的假设，即 机制取决于重复的大小。《特定目标2》将检视E46 在可用组织中寻找数量变化的转录本，异常 SCA10基因转录本的加工和异常定位。 具体目标3将通过分析E46蛋白的功能来研究 通过蛋白质印迹分析该蛋白的量和异构体，确定 通过免疫细胞化学定位蛋白质，分离相互作用的蛋白质 与正常的和异常的E46蛋白产物通过 酵母双杂交和免疫共沉淀技术及其发展 E46缺陷细胞培养模型对细胞存活、增殖和 差异化研究。从具体目标2和3获得的数据将是 与扩展的重复大小进行比较，如果适用的话。实现这些目标 特定的目标将为理解致病机理提供重要的见解 这种新的五核苷酸扩展在SCA10中的后果。

DESCRIPTION (Adapted from applicant's abstract): Spinocerebellar ataxia type 10 (SCA 10) is an autosomal dominant disease characterized by cerebellar ataxia, seizure and anticipation. The SCA1O mutation is a massive (4-22 kb) expansion of the ATTCT pentanucleotide repeat in intron 9 of E46, a novel gene of unknown function, on chromosome 22q13.3. The long-term objective of this project is to elucidate the molecular mechanisms of SCA1 0, and to develop rational treatment strategies based on the disease-causing mechanism for this progressive debilitating disease. This application will investigate the mechanism by which the expanded ATTCT repeat leads to the disease phenotype. The hypothesis of the proposed project is that an expansion of the ATTCT repeat causes the disease by altering the E46 transcript through a repeat size-dependent mechanism. SCA1 0 is one of the newly recognized dominantly inherited ataxias, and its epidemiological, clinical and genetic features have not been fully characterized. Thus, further characterization of the genotype, phenotype, and genotype-phenotype correlation in SCA10 patients needs to be the starting point of this project, and is designated as Specific Aim 1. Accomplishing this Specific Aim should strengthen our hypothesis that the disease-causing mechanism is dependent on the repeat size. Specific Aim 2 will examine the E46 transcripts in available tissues to look for quantitative changes, aberrantly processed transcripts and abnormal localization of transcripts in SCA10. Specific Aim 3 will investigate E46 protein functions by analyzing the quantities and isoforms of this protein by western blot, determining the protein localization by immuno-cytochemistry, isolating proteins that interact with the normal and, if detected, aberrant E46 protein products by yeast-two-hybrid and co-immunoprecipitation techniques, and developing E46-deficient cell culture models for cell survival, proliferation and differentiation studies. Data obtained from Specific Aims 2 and 3 will be compared with the expanded repeat size, when applicable. Accomplishing these Specific Aims will provide important insights into understanding the pathogenic consequences of this novel pentanucleotide expansion in SCA10.