Dissecting the genetic underpinnings of essential tremor

描述（由申请人提供）：本提案的长期目标是确定原发性震颤（ET）的新基因突变，以深入了解其生物学和病因学，这一点尚不清楚。ET是成人生活中最常见的神经系统疾病之一，其患病率随着年龄的增长而稳步上升。ET的主要运动症状是8- 12赫兹的姿势性或动态性手臂震颤；然而，绝大多数ET患者还会出现其他运动和非运动表现，经常导致误诊。由于大多数ET患者受益于或部分受益于药物治疗，因此及时诊断和适当治疗对于延迟或预防经常使ET患者面临经济和其他困难的功能残疾是必要的。在过去的几年里，外显子组测序（ES）已经证明了它识别遗传性疾病的因果等位基因的能力，甚至在以前被认为在统计上没有能力进行位置克隆的家庭中也是如此，并且正在成为孟德尔和更复杂性状基因识别的一种富有成效的策略。在这种情况下，由于传统的克隆技术未能确定ET的致病基因，我们坚信外显子组测序是加速特发性震颤基因发现的最合适技术。因此，基于我们之前的工作和自己的初步数据，通过使用ES可以很容易地识别疾病基因，本项目的目标是通过在临床和种族同质的ET患者群体中应用ES来识别新的震颤基因突变。使用基因同质家族将减少位点和等位基因的异质性，从而提高基因发现的统计能力。为了实施这一建议，我们收集了100多名ET患者的DNA样本，包括8个大家庭、11个小家庭和零星患者。所有建议的ET患者

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to identify novel gene mutations underlying essential tremor (ET) to gain insights into its biology and etiology, which are poorly understood. ET is one of the most common neurological diseases in adult life whose prevalence increasing steadily with age. The main motor symptom of ET is an 8- to 12-Hz postural or kinetic tremor of the arms; however, the vast majority of ET patients also develop other motor and non-motor manifestations, frequently causing misdiagnosis. Since most people with ET benefit, or partially benefit, from drug therapy, prompt diagnosis and appropriate treatment are necessary for delaying or preventing the functional disabilities that often make ET patients face financial and other difficulties. In the last few years, exome sequencing (ES) has proved its ability to identify causal alleles for inherited diseases, even in families previously deemed statistically underpowered for positional cloning, and is becoming a fruitful strategy for gene identification in both Mendelian and more complex traits. In this context, because conventional cloning techniques have failed to identify causal genes for ET, we strongly believe that exome sequencing is the most appropriate technique for accelerating gene discovery in essential tremor. Therefore, based on our previous works and own preliminary data that disease genes can readily be identified through the use of ES, the goal of the proposed project is to identify novel gene mutations underlying tremor by applying ES in a clinically and ethnically homogeneous group of patients with ET. The use of genetically homogenous families will reduce both locus and allelic heterogeneity, thus increasing statistical power for gene discovery. To carry out this proposal, we have collected DNA samples from over 100 ET patients, including eight large families, eleven small families, as well as sporadic patients. All proposed ET patients are from the same geographical region in the North of Spain and are subject to an ongoing full clinical trial that includes exhaustive clinical, neurophysiological, neuroimaging, and neuropsychological examinations. All patients developed disease symptoms before the age of 40, suggesting that genetic factors are likely to play a major role in disease development. Based on our preliminary data, we anticipate that novel gene mutations underlying ET will be identified upon completion of the proposed project, thus facilitating the understanding of tremor's overall etiology, prognosis, and treatment. In addition, we strongly believe that the identification of novl tremor genes will greatly contribute to the comprehension of other neurodegenerative diseases such as Parkinson's disease, as having ET increases the risk for developing Parkinson's disease. Lastly, since gene discovery leads directly to model systems, better understanding of pathogenesis, improved diagnostic tests, and novel targets for drug development, the proposed project will enormously contribute to the translation of basic biomedical research into clinical practice, thus benefiting human health and reducing health care cost.