Identification of a Gene Underlying Dystonia

描述（由申请方提供）：肌张力障碍是一种常见的临床和遗传异质性运动障碍。它们的特征是不自主的，持续的，重复的和模式化的肌肉收缩，影响身体的一个或多个部位，经常引起扭曲和重复运动，或异常姿势。肌张力障碍可能是由中枢神经系统结构性病变、药物、“特发性”或明显的遗传性引起的。至少有10个遗传性肌张力障碍的基因座已被定位，其中4个基因座的基因已被鉴定。 我们的长期目标是通过识别潜在的基因来剖析各种运动障碍的病理生理学，并研究这些基因在正常和疾病状态下的调节，并根据这些发现制定治疗方案。我们最近发现了一个大家族，表现出一种变异形式的肌张力障碍，似乎与震颤和阵发性肌肉痉挛分离。基于对这个大家族成员的表型评价，我们假设这个家族正在分离一种迄今未描述的肌张力障碍类型，因此，提供了一个鉴定新基因的机会。模拟分析表明，有足够的权力，以检测在这个家庭的联系。我们建议：（i）通过对已经采样的20个受影响和选定的未受影响的成员进行连锁分析，检查所有相关的已知基因座的关联性;（ii）如果排除已知基因座，则进行全基因组连锁分析，以绘制肌张力障碍基因座;以及（iii）确定候选基因并进行突变分析，以确定肌张力障碍基因。将通过参数和非参数方法进行连锁分析。候选基因将优先生物信息学和分子方法，包括一种新的定制微阵列方法。选择的候选基因的突变分析和家庭中的验证将确定dystoma基因。未来的研究将致力于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建立动物模型。我们的研究将增加有关肌张力障碍的知识库，使未来能够设计更好的诊断和治疗策略。

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.