Dissecting the genetic underpinnings of essential tremor

剖析特发性震颤的遗传基础

• 批准号: 8486941
• 负责人: Coro Paisan-Ruiz
• 金额: $ 25.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8486941
• 关键词: Adult; Affect; Age; Alleles; Biological Models; Biology; Biomedical Research; Brain; Brain Diseases; Candidate Disease Gene; Child; Clinical; Clinical Trials; Cloning; Complex; Comprehension; Consumption; DNA; Data; Development; Diagnosis; Diagnostic tests; Disease; Essential Tremor; Etiology; Face; Family; Functional disorder; Funding; Gene Mutation; Genes; Genetic; Genetic Models; Genetic Variation; Genome; Genotype; Goals; Health; Health Care Costs; Heterogeneity; Human; Individual; Inheritance Patterns; Inherited; Kinetics; Life; Molecular Profiling; Mothers; Motor; Motor Manifestations; Movement Disorders; Mutation; Neurodegenerative Disorders; Occupations; Other Genetics; Parkinson Disease; Pathogenesis; Pathogenicity; Patients; Pharmacotherapy; Phenocopy; Phenotype; Play; Prevalence; Proteins; Quality of life; Reporting; Research; Risk; Role; Sampling; Scanning; Spain; Symptoms; Techniques; Therapeutic; Translations; Tremor; Validation; Variant; Work; arm; base; clinical practice; drug development; effective therapy; exome sequencing; functional disability; gene discovery; genetic linkage analysis; genetic pedigree; improved; insight; nervous system disorder; neuroimaging; neurophysiology; neuropsychological; novel; outcome forecast; positional cloning; prevent; public health relevance; sample collection; segregation; trait

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.

描述(申请人提供)：这项建议的长期目标是确定原发性震颤(ET)潜在的新基因突变，以深入了解其生物学和病因学，目前人们对此知之甚少。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呈稳步上升趋势。ET的主要运动症状是手臂8-12赫兹的姿势或运动性震颤；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缓或预防经常使ET患者面临经济和其他困难的功能障碍是必要的。在过去的几年里，外显子组测序(ES)已经证明了它能够识别遗传病的因果等位基因，即使在以前被认为是位置克隆能力不足的家庭中也是如此，并且正在成为一种卓有成效的孟德尔和更复杂性状的基因鉴定策略。在这种背景下，由于传统的克隆技术无法识别ET的致病基因，我们强烈认为外显子组测序是加速特发性震颤基因发现的最合适的技术。因此，基于我们以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，拟议的项目的目标是通过在临床和种族相同的ET患者组中应用ES来识别潜在震颤的新的基因突变。基因同源家系的使用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能力。为了实现这一建议，我们收集了100多名ET患者的DNA样本，其中包括8个大家庭，11个小家庭，以及散发性患者。所有建议的ET患者 都来自西班牙北部的同一地理区域，正在接受全面的临床试验，包括详尽的临床、神经生理学、神经成像和神经心理学检查。所有患者在40岁之前都出现了疾病症状，这表明遗传因素可能在疾病发展中发挥主要作用。根据我们的初步数据，我们预计在拟议的项目完成后，将识别出与ET相关的新的基因突变，从而有助于了解震颤的总体病因、预后和治疗。此外，我们坚信，识别新的震颤基因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增加了发生帕金森病的风险。最后，由于基因发现直接导致模型系统，更好地了解发病机制，改进的诊断测试，以及药物开发的新靶点，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，从而造福人类健康，降低医疗成本。