Identification of a Novel Gene for Parkinson Disease

描述(申请人提供)：帕金森病(PD)是仅次于阿尔茨海默病的第二种最常见的神经退行性疾病。尽管多巴胺替代疗法改善了帕金森病的功能预后，但目前还没有阻止疾病进展的治疗方法。帕金森病的病因尚不清楚。大多数帕金森病病例是散发性的。然而，大约5%-10%的帕金森病患者可能有明确的家族史，表现出典型的隐性或显性孟德尔遗传模式。在过去的十多年里，遗传学研究在理解帕金森病的病因和发病机制方面发挥了至关重要的作用。但是，遗传研究的力量是非常有限的，因为它需要足够数量的信息减数分裂，即既有正常成员又有受影响成员的大家系，特别是当存在巨大的遗传异质性时。对于包括帕金森病在内的大多数迟发性神经退行性疾病来说，这是一项特别困难的任务。由于帕金森病是一种起病较晚的疾病，平均发病年龄在60岁到80岁之间，因此收集帕金森病大家族和DNA样本实际上是相当困难的。收集一个2-3代的PD大家族通常需要几十年的时间。因此，收集帕金森病大家系是鉴定新的帕金森病致病基因的重要障碍。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名成员的PD大家庭，其中11名成员受到影响。我们收集了62名成员的临床信息和DNA样本，包括10名受影响个人的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进行了尸检。两份尸检样本的病理分析显示帕金森病，包括典型的路易小体。但未受影响的成员没有显示帕金森病病理。这些数据表明该家系的帕金森病与特发性帕金森病相似。在美国帕金森病协会(APDA)的支持下，我们排除了目前已知的导致帕金森病的基因的突变，表明了一个新的帕金森病基因座。然后我们进行了全基因组的连锁分析。排除了已知的PD基因座，并在20号染色体的短臂上提出了一个PD连锁候选基因。本项目旨在结合最近发展的外显子组测序方法和我们在过去19年中积累的独特资源来鉴定一个新的PD致病基因。在这个帕金森病家族中确定的候选基因将在500多个家族性帕金森病先证者中进一步测试。该基因可能是常染色体显性遗传性帕金森病的第三个高外显性基因。该项目的完成不仅可能导致帕金森病遗传基础的确定，而且为帕金森病研究界提供了一个新的分子靶点，用于进一步研究帕金森病的发病机制、生物学途径和潜在的治疗策略。 公共卫生意义：帕金森病(PD)是仅次于阿尔茨海默病的第二大常见神经退行性疾病。尽管多巴胺替代疗法改善了帕金森病的功能预后，但目前还没有阻止疾病进展的治疗方法。帕金森病的病因尚不清楚。在过去的十多年里，遗传学研究在理解帕金森病的病因和发病机制方面发挥了至关重要的作用。经过19年的合作，我们已经确定了一个PD大家族，并收集了DNA样本。遗传测序和作图研究表明，常染色体显性遗传型帕金森病存在一个新的基因座。在这一应用中，我们建议使用这些独特的遗传物质和最近发展的完整外显子组测序技术来识别一个新的导致帕金森病的基因。该项目的完成可能导致发现一个新的分子靶点，用于进一步研究疾病机制、生物学途径和潜在的治疗策略。

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. PUBLIC HEALTH RELEVANCE: 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. Genetic studies in the past more than 10 years have played a vital role in understanding the etiology and pathogenic mechanism of PD. Through a 19-year collaborative effort, we have identified a large PD family and collected DNA samples. Genetic sequencing and mapping studies indicate a new locus for autosomal dominant form of PD. In this application, we propose to identify a novel PD-causing gene using these unique genetic materials and recently developed whole exome sequencing technology. Completion of this project may lead to the discovery of a novel molecular target for further studies of the disease mechanisms, biological pathways and potential therapeutic strategies.