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种最常见的神经退行性疾病。虽然多巴胺替代疗法改善了PD的功能预后，但目前还没有预防疾病进展的治疗方法。PD的病因学尚未完全了解。大多数PD病例是散发的。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。近10多年来的遗传学研究对了解PD的病因和发病机制起到了至关重要的作用。但是，遗传学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，即大家庭的正常和受影响的成员，特别是当巨大的遗传异质性存在。对于大多数迟发性神经退行性疾病，包括PD，这是一项特别困难的任务。由于PD是一种晚发性疾病，平均发病年龄在60 - 80岁之间，因此实际上很难收集大的PD家族和DNA样本。收集一个2-3代的PD大家族通常需要几十年。因此，收集大激酶与PD代表了一个重大的障碍，新的PD致病基因的鉴定。通过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大的PD家庭，有67名成员，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名受影响人员的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尸检。两个尸检样本的病理学分析显示帕金森病理学，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，PD在这个家族是类似于特发性PD。在美国帕金森病协会（APDA）的支持下，我们排除了目前已知的PD致病基因的突变，表明一个新的PD基因座。然后，我们进行了全基因组连锁分析。排除了已知的PD基因座，并建议在20号染色体的短臂上存在一个候选的PD连锁基因座。本项目旨在通过结合使用最近开发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新的PD致病基因。在这个PD家族中鉴定的候选基因将在500多个家族性PD先证者中进一步检测。该基因可能是常染色体显性遗传PD的第三个高等位基因。该项目的完成不仅可以明确PD的遗传基础，还可以为PD研究提供新的分子靶点，为进一步研究PD的发病机制、生物学通路和潜在的治疗策略提供新的分子靶点。 公共卫生相关性：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。虽然多巴胺替代疗法改善了PD的功能预后，但目前还没有预防疾病进展的治疗方法。PD的病因学尚未完全了解。近10多年来的遗传学研究对了解PD的病因和发病机制起到了至关重要的作用。通过19年的合作努力，我们已经确定了一个大的PD家族，并收集了DNA样本。基因测序和定位研究表明，一个新的基因座常染色体显性形式的PD。在本申请中，我们建议使用这些独特的遗传物质和最近开发的全外显子组测序技术来鉴定一种新的PD致病基因。该项目的完成可能会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.