Dissecting the genetic underpinnings of essential tremor

描述（由申请人提供）：该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，这是知之甚少的。ET是成年人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的主要运动症状是手臂的8- 12-Hz姿势性或运动性震颤;然而，绝大多数ET患者还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功能障碍是必要的，这些功能障碍通常使ET患者面临经济和其他困难。在过去的几年中，外显子组测序（ES）已经证明了其识别遗传性疾病的致病等位基因的能力，即使在以前被认为是统计学上不足以进行位置克隆的家庭中，并且正在成为孟德尔和更复杂性状的基因识别的富有成效的策略。在这种情况下，由于传统的克隆技术未能确定病因基因的ET，我们坚信，外显子组测序是最合适的技术，加快基因发现原发性震颤。因此，基于我们以前的工作和自己的初步数据，疾病基因可以很容易地通过使用ES识别，拟议项目的目标是通过在临床和种族同质的ET患者组中应用ES来识别震颤相关的新基因突变。使用遗传同质的家庭将减少基因座和等位基因的异质性，从而增加基因发现的统计力量。为了落实这项建议，我们收集了超过100名ET患者的DNA样本，包括8个大家庭，11个小家庭，以及散发患者。所有拟定ET患者 来自西班牙北部的同一地理区域，并正在进行全面的临床试验，包括详尽的临床，神经生理学，神经影像学和神经心理学检查。所有患者都在40岁之前出现疾病症状，这表明遗传因素可能在疾病发展中起主要作用。根据我们的初步数据，我们预计，新的基因突变的基础ET将被确定后，完成拟议的项目，从而促进了解震颤的整体病因，预后和治疗。此外，我们坚信，novl震颤基因的鉴定将极大地有助于理解其他神经退行性疾病，如帕金森病，因为ET增加了发展帕金森病的风险。最后，由于基因发现直接导致模型系统，更好地理解发病机制，改进诊断测试和药物开发的新靶点，拟议的项目将极大地促进基础生物医学研究转化为临床实践，从而有利于人类健康并降低医疗成本。

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.