Identification of novel Parkinsonian genes by wholegenome

在多代家庭中的经典连锁研究已经发现了一些含有突变基因的基因。 会导致神经退行性变。梅奥诊所尤德尔中心的调查人员成功地驾驶 许多这样的研究和基因鉴定是我们中心最大的优势之一。最近， 下一代测序技术的发展导致了基因研究的转变，使得 使用较小的家系，只有有限数量的DNA样本可用，并且显著 减少识别新基因所需的时间。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变家族集合中识别帕金森病的新基因 A-突触核病症(目标1)和变态核病(目标2)。根据是否可用来选择族 至少3名患者的DNA样本，优先包括一对受影响的表亲，尸检确认 路易体病理或tau病理，排除所有已知的常染色体显性Par-1突变。 金森氏病(PD)基因和微管相关蛋白tau基因，MAPT。新的变种将 根据突变类型确定优先顺序，并严格定义分析方式。要确定 新致病帕金森病基因中的罕见和常见变异是否会给普通人群带来风险 帕金森病与进行性核上性麻痹(PSP)患者的深入关联研究 随后将执行新的帕金森病基因(目标3)。由Candi-鉴定的编码变体 Date基因测序与所选候选基因座的单倍型标记变体相结合 来自公共数据库的数据将被包括在内。有意义的相关变异将通过评估进一步研究 它们对基因和蛋白质表达的影响，以及与tau和a-突触核蛋白的潜在相互作用。 GY。本项目中提出的新基因和遗传风险因素的发现将毫无疑问地 有助于更好地了解与tau和a-突触核蛋白动态相关的疾病机制- 在帕金森病中的作用。此外，帕金森病新基因的发现将进一步促进帕金森病的研究。 减少新的病因和症状性疾病模型的开发，在这些模型中，新的治疗方法可以 已评估。 相关性(请参阅说明)： 这项建议旨在确定帕金森氏症和a-突触核蛋白或 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症患者的能力，去... 开发新的病因学疾病模型并增加对相关疾病机制的理解 伴有tau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.