Identification of a Novel Gene for Parkinson Disease

描述（由申请人提供）：帕金森病（PD）是仅次于阿尔茨海默病的第二常见神经退行性疾病。虽然多巴胺替代疗法改善了PD的功能预后，但目前还没有一种治疗方法可以阻止疾病的进展。PD的病因尚不清楚。大多数PD病例是散发性的。然而，大约5-10%的PD患者可能有明确的家族史，表现出经典的隐性或显性孟德尔遗传模式。过去十多年来的遗传学研究对了解帕金森病的病因和发病机制起着至关重要的作用。但是，遗传研究的力量受到很大的限制，因为它需要足够数量的信息减数分裂，即大家庭中既有正常成员，也有患病成员，特别是当存在很大的遗传异质性时。对于大多数晚发性神经退行性疾病，包括帕金森病，这是一项特别困难的任务。由于帕金森病是一种迟发性疾病，平均发病年龄在60 - 80岁之间，因此收集大的帕金森病家族和DNA样本实际上相当困难。一个有2-3代人的PD家族的收集通常需要几十年的时间。因此，收集PD的大型种类代表了鉴定新的PD致病基因的重大障碍。通过从1992年开始的19年的合作努力，我们和我们的合作者已经确定了一个有67个成员的PD大家庭，其中11个成员受到影响。我们收集了62名成员的临床信息和DNA样本，其中包括10名受影响个体的DNA样本。在此期间，两名受影响的成员和一名未受影响的成员死亡并被尸检。两个尸检样本的病理分析显示帕金森病理，包括典型的路易体。但未受影响的成员没有表现出PD病理。这些数据表明，该家族的PD与特发性PD相似。由美国帕金森病协会（APDA）支持；我们排除了目前已知的PD致病基因的突变，这表明存在一种新的PD位点。然后我们进行了全基因组连锁分析。我们排除了已知的pd位点，在20号染色体短臂上发现了一个pd连锁位点。该项目旨在结合最近开发的外显子组测序方法和我们过去19年积累的独特资源，鉴定一种新的pd引起基因。在该PD家族中发现的候选基因将在超过500个家族PD先证者中进一步测试。该基因可能是常染色体显性帕金森病的第三个高外显率基因。本项目的完成，不仅可能为PD家族的遗传基础的鉴定提供新的分子靶点，为进一步研究PD的发病机制、生物学途径和潜在的治疗策略提供新的分子靶点。

DESCRIPTION (provided by applicant): Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Although dopamine replacement therapy improves the functional prognosis of PD, there is currently no treatment that prevents the progression of the disease. The etiology of PD is not well understood. Most of the PD cases are sporadic. However, approximately 5-10% of PD patients may have a clear familial history, exhibiting a classical recessive or dominant Mendelian mode of inheritance. Genetic studies in the past more than 10 years have played a vital role in understanding the etiology and pathogenic mechanism of PD. But, the power of genetic study is greatly limited because it requires sufficient number of informative meiosis, i.e. large families with both normal and affected members, especially when great genetic heterogeneity exists. It is particularly a difficult task for most of the late onset neurodegenerative disorders, including PD. Because PD is a late-onset disease with an average age of onset between 60 and 80 years, it is practically rather difficult to collect large PD families and DNA samples. Collection of a large PD family with 2-3 generations normally takes decades. Thus, collection of the large kindreds with PD represents a significant hurdle for identification of new PD-causing genes. Through a 19-year collaborative effort initiated from 1992, we and our collaborators have identified a large PD family with 67 members, among whom 11 members are affected. We have collected clinical information and DNA samples from 62 members, including DNA samples from 10 affected individuals. During this period, two affected and one unaffected members died and were autopsied. Pathological analysis of the two autopsy samples revealed Parkinson pathology, including typical Lewy bodies. But the unaffected member did not show PD pathology. These data suggest that the PD in this kindred is similar to idiopathic PD. Supported by the American Parkinson Disease Association (APDA); we excluded mutations in currently known PD-causing genes, indicating a novel PD locus. We then carried out a genome-wide linkage analysis. The known PD-loci were excluded and a candidate PD-linked locus was suggested on the short arm of chromosome 20. This project is designed to identify a novel PD-causing gene by combined use of the recently developed exome sequencing approach and the unique resources that we have accumulated in the past 19 years. The candidate gene identified in this PD family will be further tested in over 500 familial PD probands. This gene may represent the third gene with a high penetrance for autosomal dominant PD. Completion of this project may not only lead to identification of the genetic basis of PD in this kindred, but also provides the PD research community with a novel molecular target for further studies of the disease mechanisms, biological pathways and potential therapeutic strategies.