Identification of novel Parkinsonian genes by wholegenome

在多代家庭中进行的经典连锁研究已经确定了许多携带穆塔的基因- 会导致神经退化马约诊所尤德尔中心的研究人员成功地推动了 其中许多研究和基因鉴定是我们中心最大的优势之一。近日 下一代测序技术的发展导致了遗传学研究的转变， 使用较小的谱系，只有有限数量的DNA样本可用， 从而缩短了识别新基因的时间。我们的项目开始使用全基因组测序 在我们独特的神经退行性疾病家族中， α-突触核蛋白病（Aim 1）和tau蛋白病（Aim 2）。族的选择基于以下方面的可用性： 来自至少3名受影响者的DNA样本，优先包括受影响的双胞胎，尸检确认 路易体病理学或tau病理学的突变，并排除所有已知的常染色体显性Par 帕金森病（PD）基因和微管相关蛋白tau基因，MAPT。新变种将 根据突变类型确定优先级，并以严格定义的方式进行分析。以确定 新的致病帕金森病基因中的罕见和常见变异是否会给一般的帕金森病患者带来风险， PD和进行性核上性麻痹（PSP）患者人群，深入关联研究 新的帕金森病基因将随后进行（目的3）。编码变体由candi- 日期基因测序结合所选候选基因座的单倍型标记变体 公共数据库将被纳入。将通过评估进一步研究显著相关的变体 它们对基因和蛋白质表达的影响，以及与tau蛋白和α-突触核蛋白生物学的潜在相互作用， 戈伊。本项目提出的新基因和遗传风险因素的发现，无疑将 有助于更好地理解与tau和a-突触核蛋白dys相关的疾病机制， 在帕金森病中的作用此外，新的帕金森病基因的鉴定将进一步 降低了新的病因和症状疾病模型的发展，其中新的治疗方法可以 评估。 相关性（参见说明）： 该建议旨在确定帕金森综合征和α-突触核蛋白或α-突触核蛋白家族中的新致病基因。 使用全基因组测序的tau病理学。拟议的研究将有助于我们了解 我们通过改善患者诊断来治疗帕金森病患者的能力， 开发新的病因学疾病模型，并增加对相关疾病机制的理解 tau蛋白和α-突触核蛋白功能障碍

Classic linkage studies in multigenerational families have identified a number of genes that harbor muta- tions that cause neurodegeneration. The Mayo Clinic Udall Center investigators have successfully driven many of these studies and gene identification is one of the greatest strengths of our Center. Recently, the development of next-generation sequencing technologies has led to a shift in genetic studies, allowing the use of smaller pedigrees for which only a limited number of DNA samples are available and dramatically reducing the time it takes to identify new genes. Our Project sets out to use whole-genome sequencing in our unique collection of families with neurodegeneration to identify novel genes for Parkinsonian a-synucleinopathies (Aim 1) and tauopathies (Aim 2). Families are selected based on the availability of DNA samples from at least 3 affecteds, preferentially including an affected cousin-pair, autopsy confirmation of Lewy-body pathology or tau pathology, and exclusion of mutations in all known autosomal dominant Par- kinson's disease (PD) genes and the microtubule associated protein tau gene, MAPT. Novel variants will be prioritized based on the type of mutation and analyzed in a strictly defined manner. To determine whether rare and common variants in novel causal Parkinsonian genes confer risk to the general population of PD and progressive supranuclear palsy (PSP) patients, in-depth association studies of novel Parkinsonian genes will subsequently be performed (Aim 3). Coding variants identified by candi- date gene sequencing combined with haplotype-tagging variants across the candidate gene loci selected from public databases will be included. Significantiy associated variants will be further studied by assessing their influence on gene and protein expression, and the potential interaction with tau and a-synuclein biolo- gy. The discovery of novel genes and genetic risk factors, as proposed in this Project, will unquestionably contribute to a better understanding of the disease mechanism associated with tau and a-synuclein dys- function in Parkinsonian disorders. Moreover, the identification of novel Parkinsonian genes will further al- low the development of novel etiologic and symptomatic disease models in which new therapies can be evaluated. RELEVANCE (See instructions): This proposal is designed to identify novel causal genes in families with Parkinsonism and a-synuclein or tau pathology using whole-genome sequencing. The proposed studies will contribute to our understanding of and our ability to treat patients with Parkinsonism through improved patient diagnosis, the ability to de- velop novel etiologic disease models and an increased understanding of the disease mechanism associated with tau and a-synuclein dysfunction.