MOLECULAR GENETICS OF DOPA-RESPONSIVE DYSTONIA

这个项目的重点是定位“多巴反应性肌张力障碍”的基因。 (DRD)，一种常染色体显性遗传病。这种疾病是一个不同的子集 儿童期起病的特发性扭转肌张力障碍(ITD)，但有几个 将其与ITD区分开来的功能。在某些情况下，它可能具有以下功能 提示脑性瘫痪，在临床进展之前应该允许 疾病的分离。对两个家庭的分析表明，成年人 发作性帕金森病可能是基因携带者的临床表型 在儿童时期不会表现出肌张力障碍。这一发现可能具有临床意义 与某些遗传性帕金森综合征的相关性。 我们建议对已知的最大的亲缘关系--S家族进行连锁分析 受DRD影响，确定与DRD连锁的染色体区域。我们会 然后在该地区使用已知标记的饱和度测绘或开发新的 通过选择性克隆方法进一步界定专性基因的标记 DRD基因的区域(OGR)。然后我们就可以测试基因的异质性 与其他较小的DRD家庭一起。 OGR的物理地图将通过PULSE等技术构建 现场凝胶电泳和染色体“行走”。编码序列将 通过几种克隆和杂交策略进行鉴定 正常人与患者DNA中“候选区域”的比较 试图找出病源。 识别DRD的基因可能有助于更好地了解 DRD的生化缺陷。提高了儿童时期的诊断可靠性 肌张力障碍和某些形式的成人发作性帕金森综合症应 有可能。

This project is focused on locating the gene for "dopa-responsive dystonia" (DRD), an autosomal dominant disorder. This disorder is a distinct subset of childhood-onset, idiopathic torsion dystonia (ITD), but has several features that separate it from ITD. In some cases it may have features suggestive of cerebral palsy, before clinical progression should allow separation of the disorders. Analysis of two families suggests that adult onset parkinsonism may be the clinical phenotype of gene carriers who do not manifest dystonia in childhood. This finding may have clinical relevance in some cases of hereditary parkinsonism. We propose to do linkage analysis on "Family S," the largest known kindred affected with DRD, to identify a chromosomal region linked to DRD. We will then use saturation mapping with known markers in the region or develop new markers by selective cloning methods to further delimit an obligate genetic region (OGR) for the DRD gene. We can then test for genetic heterogeneity with other smaller DRD families. A physical map of the OGR will be constructed by techniques such as pulse field gel electrophoresis and chromosome "walking." Coding sequences will be identified by several cloning and hybridization strategies and "candidate regions" compared in DNA between normal and affected individuals in an attempt to identify the disease locus. Identification of the gene for DRD may allow better understanding of the biochemical defect in DRD. Improved diagnostic reliability in childhood dystonic conditions and some forms of adult-onset parkinsonism should be possible.