Identification of a Gene Underlying Dystonia

肌张力障碍基因的鉴定

• 批准号: 6936235
• 负责人: Pragna Patel
• 金额: $ 12.51万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936235
• 关键词: DNA; abnormal involuntary movement; brain disorder diagnosis; clinical research; computer simulation; degenerative motor system disease; diagnosis design /evaluation; dystonia; family genetics; gene expression; gene mutation; genetic mapping; genetic regulation; genetic screening; genotype; human genetic material tag; human subject; informatics; information systems; linkage mapping; microarray technology; neurogenetics; neuromuscular disorder; phenotype; polymerase chain reaction; posture

DESCRIPTION (provided by applicant): The dystonias are a common clinically and genetically heterogeneous group of movement disorders. They are characterized by involuntary, sustained, repetitive and patterned muscle contractions, affecting one or more sites of the body, frequently causing twisting and repetitive movements, or abnormal postures. Dystonia may be caused by CNS structural lesions, medications, be "idiopathic" or demonstrate obvious genetic inheritance. At least ten loci for inherited forms of dystonia have been mapped and genes have been identified at four of these loci. Our long-term goal is to dissect the pathophysiology of various movement disorders by identifying the underlying genes, and studying the regulation of these genes in the normal and disease state and to develop treatment regimens based on these findings. We have recently identified a large family demonstrating a variant form of dystonia that appears to segregate with tremor and paroxysmal muscle spasms. Based on phenotypic evaluation of members of this extended family, we hypothesize that this family is segregating a hitherto undescribed type of dystonia and thus, provides an opportunity to identify a new gene. Simulation analysis indicates sufficient power to detect linkage in this family. We propose to (i) examine all relevant known loci for association by linkage analysis of 20 affected and selected unaffected members that have already been sampled (ii) conduct genome-wide linkage analysis to map the dystonia locus if known loci are excluded, and (iii) identify candidate genes and conduct mutation analysis in order to identify the dystoma gene. Linkage analysis will be conducted by parametric and non-parametric approaches. Candidate genes will be prioritized by bioinformatics and molecular approaches including a novel custom microarray approach. Mutation analysis of selected candidate genes and validation in the family will identify the dystoma gene. Future studies will aim to dissect the biochemistry and cell biology of the gene product, and to develop an animal model for this form of dystonia. Our studies will add to the repertoire of knowledge about dystonia that should enable design of better diagnostic and treatment strategies for dystoma in the future.

描述（由申请人提供）：肌张力障碍是一种临床和遗传上异质运动障碍的常见。它们的特征是非自愿，持续，重复和图案的肌肉收缩，影响身体的一个或多个部位，经常引起扭曲和重复的运动或异常的姿势。肌张力障碍可能是由CNS结构性病变，药物，特发性引起的，或者表现出明显的遗传遗传。已经映射了至少十个遗传形式的肌张力障碍的基因座，并在其中四个基因座进行了鉴定。 我们的长期目标是通过鉴定潜在的基因来剖析各种运动障碍的病理生理学，并研究正常和疾病状态下这些基因的调节，并根据这些发现开发治疗方案。我们最近确定了一个大型家庭，展示了一种变异形式的肌张力障碍，似乎会因震颤和阵发性肌肉痉挛而隔离。基于对这个大家庭成员的表型评估，我们假设该家族正在隔离迄今未描述的肌张力障碍类型，因此提供了一个识别新基因的机会。仿真分析表明有足够的能力来检测该家族的联系。我们建议（i）通过对已经进行了采样的20个受影响和未受影响的成员进行连锁分析（II）进行全基因组链接分析以绘制肌张力障碍基因座（如果排除已知基因座），（iii）确定候选基因并进行突变分析以识别肌瘤基因的突变分析。链接分析将通过参数和非参数方法进行。候选基因将通过生物信息学和包括新颖的自定义微阵列方法在内的分子方法来优先。对家族中选定的候选基因和验证的突变分析将鉴定出肌瘤基因。未来的研究将旨在剖析基因产物的生物化学和细胞生物学，并为这种形式的肌张力障碍开发动物模型。我们的研究将增加有关肌张力障碍知识的曲目，该曲目应在未来设计出更好的诊断和治疗策略。