Analysis of monogenic essential Tremor by exome sequencing.

通过外显子组测序分析单基因特发性震颤。

• 批准号: 258890088
• 负责人: Professor Dr. Günther Deuschl
• 金额: --
• 依托单位: Institut für Klinische Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/258890088?language=en
• 关键词: Analysis; monogenic; essential; Tremor; exome

Essential Tremor (ET) is with a lifetime prevalence of >1% in the general population the second most common movement disorder. The Department of Neurology and my workgroup at the University of Kiel are a leading center for the clinical, pathophysiological and genetic investigation of ET. Clinically, ET is characterized by a postural and in addition often also a kinetic tremor which is debilitating in severe cases. The pathophysiologic basis of ET is largely unknown. A functional hypothesis proposing abnormal oscillatory activity generated in the brain stem competes with a neurodegenerative hypothesis. ET is in most cases genetically complex with a high heritability. In the preceding project we performed a genome wide association study (GWAS) for ET and identified genetic risk variants in the major glutamate reuptake transporter (SLC1A2). A second, much larger GWAS in cooperation with the universities of Tübingen, Innsbruck and Vienna will soon be finished. In a minority of cases ET the inheritance pattern is compatible with autosomal dominant inheritance. Conventional genetic strategies like linkage-analysis have not been able to reveal the causes of monogenic ET. Among the causes for this failure might be the lack of numerous very large families, phenocopies, reduced penetrance and locus-heterogeneity. One ET-candidate gene (fused in sarcoma, FUS) for monogenic ET has recently been identified by exome sequencing. The identification of additional genetic variants causing monogenic ET is extremely important because monogenic forms of common disease are often invaluable models for the pathomechanism of their common polygenic counterparts. In cooperation with groups from Austria, Germany and France we have examined 56 families with three or more members definitively affected by ET. Exome sequencing is a powerful method to identify disease causing mutations in monogenic disorders if large numbers of families are analyzed and appropriate variant filtering strategies are applied. The large number of families will identify causative genes even if in the presence of high locus heterogeneity. Excellent technical sequencing quality, state of the art bioinformatics and competitive pricing will be guaranteed through this joint proposal together with the Institute of Clinical Molecular Biology (IKMB) at the University of Kiel which houses one of the largest Next-Generation-Sequencing facilities in Germany. Our workgroups have already gained published experience in exome sequencing projects and have identified novel genes for monogenic disorders using conventional linkage based approaches. We are confident, that our project will identify one or more genes implied in the pathogenesis of ET.

特发性震颤 (ET) 是第二常见的运动障碍，在普通人群中终生患病率 >1%。基尔大学神经病学系和我的工作组是 ET 临床、病理生理学和遗传学研究的领先中心。 临床上，ET 的特征是姿势性震颤，此外通常还有运动性震颤，严重时会使人衰弱。 ET 的病理生理学基础很大程度上未知。提出脑干中产生异常振荡活动的功能假说与神经退行性假说相竞争。在大多数情况下，ET 的基因复杂且具有高遗传力。在之前的项目中，我们对 ET 进行了全基因组关联研究 (GWAS)，并确定了主要谷氨酸再摄取转运蛋白 (SLC1A2) 中的遗传风险变异。与蒂宾根大学、因斯布鲁克大学和维也纳大学合作的第二个规模更大的 GWAS 即将完成。在少数 ET 病例中，遗传模式与常染色体显性遗传兼容。连锁分析等传统遗传策略无法揭示单基因 ET 的原因。造成这种失败的原因可能是缺乏大量非常大的家族、表型、外显率降低和位点异质性。最近通过外显子组测序鉴定出了单基因 ET 的一种 ET 候选基因（融合在肉瘤中，FUS）。鉴定导致单基因 ET 的其他遗传变异极其重要，因为常见疾病的单基因形式通常是其常见多基因对应物的病理机制的宝贵模型。我们与奥地利、德国和法国的团体合作，检查了 56 个家庭，其中有 3 名或更多成员明确受到外星人影响。如果分析大量家族并应用适当的变异过滤策略，外显子组测序是识别单基因疾病致病突变的有效方法。即使存在高度的基因座异质性，大量的家族也会识别出致病基因。通过与基尔大学临床分子生物学研究所 (IKMB) 的联合提案，将保证卓越的技术测序质量、最先进的生物信息学和有竞争力的价格，基尔大学拥有德国最大的下一代测序设施之一。我们的工作组已经在外显子组测序项目中获得了已发表的经验，并使用基于传统连锁的方法鉴定了单基因疾病的新基因。我们相信，我们的项目将鉴定出 ET 发病机制中隐含的一个或多个基因。