Assessment of Candidate Loci in Parkinson's disease

帕金森病候选基因座的评估

• 批准号: 7135618
• 负责人: Andrew B Singleton
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7135618
• 关键词: Parkinson' s disease; alpha synuclein; disease /disorder onset; family genetics; gene duplication; genetic mapping; genetic polymorphism; genetic regulation; genetic regulatory element; genetic screening; genetic susceptibility; human genetic material tag; human subject; informatics; molecular pathology; neurogenetics; neuropathology; parkin gene /protein; patient oriented research; polymerase chain reaction

Parkinson's disease (PD) was long considered the archetypal non-genetic disease entity. A combination of increased understanding of complex genetics and the use of isolated populations has clarified that genetics plays a significant role in the risk of PD. We are assessing the role of genetics in PD usign two approaches, firstly a case-control association study and secondly a mutation screening approach. Using well characterized patient and control cohorts from Finland we are utilizing a case control methodology to elucidate the role of candidate loci in PD. Consideration of genetic loci for assessment is based on prior association, gene function or genetic localization. Genetic variation such as single nucleotide polymorphisms and simple tandem repeats will be initially identified in genes of interest by web-based data mining techniques with the assistance of the bioinformatics core of LNG. Although non-functional variation is useful for constructing haplotypes across genes we will initially prioritise variation by functional relevance. To maximise the likelihood of identifying functional variation regions of high conservation across mammalian species will be initially targeted, with emphasis on promoter regions. To date we have assessed varation within the genes encoding inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), alpha-synuclein, GTP cyclohydrolase, parkin, Tau, APO E, DJ-1, UCH-L1, FRM1, SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, DRPLA, BDNF, FGF20, DYT1, and NAT2. Results identifying a consistent protective effect against PD of variation within the iNOS gene is currently in press at neurology. Likewise the first assessment of the DJ-1 gene as a risk factor for typical PD is also in press. In the previous 4 years we have collected a large series of patients with a strong family history of PD. We assess these cases for mutations within genes associated with parkinsonism, including the SCA genes, alpha-synuclein, DJ-1, parkin and GTP-cyclohydrolase. These genes are assessed by a combination of direct sequencing and semi-quantitative real-time PCR amplification. We have shown that mutations in DJ-1 are a rare (<1%) cause of young-onset PD and that disease caused by mutation at this locus can present without family history. In 2003 we identified a triplication of the alpha-synuclein gene as a cause of PD in a large well-characterized family with autosomal dominant disease. THis work provided the first mechanistic link between alpha-synuclein and Parkinson's disease. Recently we have been led a project which aimed to assess the incidence of PINK1 mutations in Parkinson;s disease and have published data which suggests these mutations are a rare cause of young onset disease.

帕金森病（PD）长期以来被认为是典型的非遗传性疾病实体。随着对复杂遗传学的深入了解和对孤立人群的使用，已经阐明遗传学在帕金森病风险中发挥着重要作用。我们正在使用两种方法评估遗传学在帕金森病中的作用，首先是病例对照关联研究，其次是突变筛查方法。利用来自芬兰的特征明确的患者和对照队列，我们​​正在利用病例对照方法来阐明候选基因座在 PD 中的作用。用于评估的遗传位点的考虑是基于先前的关联、基因功能或遗传定位。在 LNG 生物信息学核心的帮助下，通过基于网络的数据挖掘技术，将初步鉴定感兴趣基因中的单核苷酸多态性和简单串联重复等遗传变异。尽管非功能变异对于构建跨基因的单倍型很有用，但我们最初将根据功能相关性对变异进行优先级排序。为了最大限度地提高识别跨哺乳动物物种的高度保守的功能变异区域的可能性，将首先瞄准启动子区域。迄今为止，我们已经评估了编码诱导型一氧化氮合酶 (iNOS)、神经元一氧化氮合酶 (nNOS)、α-突触核蛋白、GTP 环水解酶、parkin、Tau、APO E、DJ-1、UCH-L1、FRM1、 SCA1、SCA2、SCA3、SCA6、SCA7、SCA8、SCA12、SCA17、 DRPLA、BDNF、FGF20、DYT1 和 NAT2。确定 iNOS 基因变异对 PD 具有一致保护作用的结果目前正在神经病学杂志上发表。同样，对 DJ-1 基因作为典型 PD 危险因素的首次评估也正在出版中。在过去 4 年中，我们收集了大量具有明显 PD 家族史的患者。我们评估这些病例中与帕金森病相关的基因突变，包括 SCA 基因、α-突触核蛋白、DJ-1、parkin 和 GTP-环化水解酶。这些基因通过直接测序和半定量实时 PCR 扩增相结合的方式进行评估。我们已经证明，DJ-1 突变是年轻发病 PD 的罕见（<1%）原因，并且由该位点突变引起的疾病可以在没有家族史的情况下出现。 2003 年，我们在一个特征明确的常染色体显性遗传病家族中发现，α-突触核蛋白基因的三倍体是导致 PD 的原因。这项工作首次揭示了 α-突触核蛋白与帕金森病之间的机制联系。最近，我们领导了一个项目，旨在评估帕金森病中 PINK1 突变的发生率，并发表的数据表明这些突变是年轻发病疾病的罕见原因。