Genes and susceptibility factors in primary torsion dystonia

原发性扭转肌张力障碍的基因和易感因素

• 批准号: 8854420
• 负责人: Laurie J. Ozelius
• 金额: $ 28.71万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8854420
• 关键词: Accounting; Adult; Adult-Onset Dystonias; African American; Age; Amish; Ashkenazim; Asians; Candidate Disease Gene; Caucasians; Cells; Clinical; Contracture; DNA Resequencing; Databases; Disease; Dystonia; Dystonia Musculorum Deformans; Early Onset Dystonia; Environmental Exposure; Etiology; European; Family; Focal Dystonias; Founder Effect; Frequencies; Functional disorder; General Population; Generations; Genes; Genetic; Genomic Segment; Grant; Incidence; Individual; Inherited; Maps; Mennonite; Modeling; Molecular; Molecular Profiling; Movement Disorders; Muscle; Mutation; Neck; Nerve Degeneration; Pathway interactions; Patients; Penetrance; Population; Predisposition; Prevalence; Primary Dystonias; RNA Interference; Research; Risk; Risk Factors; Role; Signal Transduction; Susceptibility Gene; Symptoms; TOR1A gene; Testing; Tremor; Variant; animal data; autosomal dominant trait; base; case control; clinical phenotype; cohort; early onset; exome sequencing; fly; follower of religion Jewish; gene function; genome wide association study; genome-wide analysis; induced pluripotent stem cell; insight; novel; outcome forecast; risk variant; screening; segregation; therapeutic target; transcription factor

Summary Primary torsin dystonias (PTD) are a group of movement disorders characterized by twisting muscle contractures, where dystonia is the only clinical sign (except for tremor) and there is no evidence of neuronal degeneration or an acquired cause. Eleven genes have been mapped for primary dystonia including DYT1 (TOR1A), 2, 4 (TUBB4A), 6 (THAP1), 7, 13, 17, 21, 23 (CIZ1), 24 (ANO3) and 25 (GNAL), however only 3 have mutations in early onset dystonia patients, TOR1A, THAP1 and GNAL. Each is inherited as an autosomal dominant trait but with reduced penetrance, meaning that individuals can carry the mutation but do not show clinical symptoms. The most common form of PTD is adult onset focal accounting for about 90% of all cases of dystonia with a prevalence estimated at 30/100,000 in the general population. A small percentage of focal cases are due to mutations in CIZ1, ANO3, THAP1, TUBB4A and GNAL but the vast majority is unaccounted for and is most likely multigenic or multifactorial. In this grant, focusing on early onset PTD, we will uncover genes that influence the penetrance of DYT1 dystonia through GWAS and exome sequencing studies. We will identify other genes for early onset PTD using exome sequencing and determine whether variants within the identified early onset PTD genes or the pathways associated with these genes contribute to susceptibility in the most prevalent form of PTD, focal dystonia, using a case:control association study. The proposed research will identify novel PTD risk factors and genes, which in turn should reveal shared and intersecting pathways leading to a better understanding of the molecular basis of PTD and provide the underpinnings for developing new treatments. Additionally, insight into the factors that modulate disease penetrance would be a first step in determine whether these could be modified leading to a reduced incidence of the disease.

概括 原发性扭转肌张力障碍 (PTD) 是一组以扭转为特征的运动障碍 肌肉挛缩，肌张力障碍是唯一的临床症状（震颤除外），并且没有 神经元变性或后天原因的证据。已绘制出 11 个基因图谱 原发性肌张力障碍包括 DYT1 (TOR1A)、2、4 (TUBB4A)、6 (THAP1)、7、13、17、21、23 (CIZ1)、 24 (ANO3) 和 25 (GNAL)，但在早发性肌张力障碍患者中只有 3 个有突变， TOR1A、THAP1 和 GNAL。每一个都作为常染色体显性遗传，但减少 外显率，意味着个体可以携带突变但不表现出临床症状。 PTD 最常见的形式是成人发病的局灶性病变，约占所有 PTD 病例的 90% 肌张力障碍在一般人群中的患病率估计为 30/100,000。一个小 局灶性病例的百分比是由于 CIZ1、ANO3、THAP1、TUBB4A 和 GNAL 突变所致，但 绝大多数都下落不明，很可能是多基因或多因素造成的。在这笔赠款中， 聚焦早发型PTD，我们将揭示影响DYT1外显率的基因 通过 GWAS 和外显子组测序研究发现肌张力障碍。我们将识别早期的其他基因 使用外显子组测序来确定发生 PTD 并确定早期识别的变异是否存在 发病 PTD 基因或与这些基因相关的途径有助于易感性 PTD 最常见的形式是局灶性肌张力障碍，采用病例对照关联研究。这 拟议的研究将确定新的 PTD 风险因素和基因，从而揭示 共享和交叉的途径可以更好地理解分子基础 PTD 并为开发新疗法提供基础。此外，深入了解 调节疾病外显率的因素将是确定这些因素是否可以 进行修改可降低该病的发病率。