Identification of a Gene Underlying Dystonia

描述（由申请人提供）：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的运动，或异常的姿势。肌张力障碍可能由中枢神经系统结构病变、药物、“特发性”或明显的遗传引起。至少十个遗传形式的肌张力障碍的基因位点已经被绘制出来，其中四个基因位点已经被鉴定出来。

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.