Elucidating and understanding the genetic basis of movement disorders

阐明和理解运动障碍的遗传基础

• 批准号: 8841023
• 负责人: Coro Paisan-Ruiz
• 金额: $ 37.08万
• 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: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8841023
• 关键词: Affect; Alleles; Biomedical Research; Brain; Cerebral Palsy; Clinical; Collaborations; Communities; Complex; DNA; Data; Databases; Development; Diagnosis; Differential Diagnosis; Disease; Dystonia; Early Diagnosis; Eating; Employee Strikes; Ethnic Origin; Etiology; Family; Functional disorder; Future; Genes; Genetic; Genetic study; Genomic Segment; Genotype; Goals; Health; Hereditary Spastic Paraplegia; Heterogeneity; Human; Inherited; International; Iron; Knowledge; Lead; Link; Medical Genetics; Medical center; Mendelian disorder; Molecular; Molecular Target; Motor Activity; Movement Disorders; Mutate; Mutation; Myoclonus; Nerve Degeneration; Neurologic; New York; PLA2G6 gene; Parkinson Disease; Parkinsonian Disorders; Pathologic Processes; Pathology; Pathway interactions; Patient Recruitments; Patients; Phenotype; Publishing; Quality of life; Recruitment Activity; Research; Research Personnel; Sampling; Seitelberger' s Disease; Spastic Paraplegia; Technology; Therapeutic; Tremor; Validation; Variant; Walking; Work; base; clinical practice; daily functioning; disease-causing mutation; drug development; exome sequencing; gene discovery; genetic linkage analysis; improved; next generation sequencing; novel; positional cloning; prevent; sample collection; segregation; sensory neuropathy; success; tool; trait; working group

DESCRIPTION (provided by applicant): Complex movement disorders (CMDs), defined as disorders in which patients are affected by more than one movement disorder (such as parkinsonism and dystonia, or myoclonus and tremor), are a continuing challenge for diagnosis and treatment. CMDs are usually progressive, prevent patients from performing basic daily functions such as walking, eating, and talking, and result in high disease-associated financial and personal burden for patients and their families. Moreover, the already-known phenotypic and etiologic heterogeneity associated with movement disorder genes is quite striking and presents a significant challenge for treatment. Therefore, early diagnosis is crucial for appropriate treatment to restore motor activities and improve patients' quality of life. Since genetic studies in movement disorders (MDs) have demonstrated their success in the discovery of underlying pathologic processes and have helped researchers to understand both disease manifestation and progression, the identification of genetic factors underlying, or contributing to, the development of MDs provides a powerful tool for understanding their associated pathology. Accordingly, in an attempt to identify molecular networks associated with these CMDs and to facilitate novel treatments, this proposal focuses on the recruitment of familial and sporadic patients with CMDs, and the identification of their disease-causing alleles. Because whole exome sequencing (WES) has proved its ability to identify causative alleles for inherited diseases, even in families previously deemed statistically underpowered for positional cloning, and has become a fruitful strategy for gene identification in both Mendelian and more complex traits, WES, along with SNP-based arrays, which will reduce the search for causal variants, will be used for disease- causing mutation identification in this proposal. We believe that intense study of these disorders represents a powerful approach to elucidate disease mechanism for both CMDs and for more common disorders such as Parkinson's disease, and will lead to improvements in both diagnoses and treatments. In conclusion, this study will contribute enormously to the identification of novel CMD genes and the characterization of their phenotype, which not only are essential for understanding the etiology and pathophysiology of CMDs, but also for developing more targeted and efficient therapeutic strategies that will be of great benefit to human health.

描述（由申请人提供）： 复杂运动障碍 (CMD) 被定义为患者受到一种以上运动障碍影响的疾病（例如帕金森症和肌张力障碍，或肌阵挛和震颤），是诊断和治疗的持续挑战。 CMD 通常是进行性的，妨碍患者执行基本的日常功能，如行走、进食和说话，并给患者及其家人带来与疾病相关的较高经济和个人负担。此外，已知的与运动障碍基因相关的表型和病因异质性是相当惊人的，并对治疗提出了重大挑战。因此，早期诊断对于适当的治疗以恢复运动能力和改善患者的生活质量至关重要。由于运动障碍 (MD) 的遗传学研究已证明其在发现潜在病理过程方面取得了成功，并帮助研究人员了解疾病的表现和进展，因此识别潜在或促成 MD 发展的遗传因素为了解其相关病理学提供了强大的工具。因此，为了试图识别与这些 CMD 相关的分子网络并促进新的治疗，该提案的重点是招募患有 CMD 的家族性和散发性患者，并鉴定其致病等位基因。因为全外显子组测序 (WES) 已证明其能够识别遗传性疾病的致病等位基因，即使是在以前被认为具有统计学意义的家庭中 定位克隆的能力不足，并且已成为孟德尔和更复杂性状的基因鉴定的一种富有成效的策略，WES 与基于 SNP 的阵列一起，将减少对因果变异的搜索，将在本提案中用于致病突变的鉴定。 我们相信，对这些疾病的深入研究代表了阐明 CMD 和帕金森病等更常见疾病的疾病机制的有力方法，并将导致诊断和治疗的改进。总之，这项研究将对新的CMD基因的鉴定及其表型的表征做出巨大贡献，这不仅对于了解CMD的病因学和病理生理学至关重要，而且对于开发更有针对性和更有效的治疗策略，对人类健康大有裨益。