MOLECULAR GENETICS OF DOPA-RESPONSIVE DYSTONIA

该项目的重点是定位基因的“多巴反应性肌张力障碍” (DRD)是一种常染色体显性遗传病。 这种疾病是 儿童期发作的特发性扭转肌张力障碍（ITD），但有几个 这些特征将其与ITD区分开来。 在某些情况下，它可能具有 提示脑瘫，在临床进展之前， 疾病的分离。 对两个家庭的分析表明， 帕金森病发作可能是基因携带者的临床表型， 在儿童时期没有明显的肌张力障碍。 这一发现可能具有临床意义。 与某些遗传性帕金森症有关 我们建议对已知最大的家族S进行连锁分析 受DRD影响，以确定与DRD相关的染色体区域。 我们将 然后使用该地区已知标记的饱和度映射或开发新的 通过选择性克隆的方法进一步划定专性遗传标记， DRD基因的OGR区。 然后我们可以测试遗传异质性 与其他较小的DRD家庭。 OGR的物理图将通过脉冲等技术构建， 场凝胶电泳和染色体步移。“编码序列将 通过几种克隆和杂交策略进行鉴定， “候选区域”在正常和受影响的个体之间的DNA比较 试图找出致病基因 DRD基因的鉴定可能有助于更好地理解DRD的基因表达。 DRD的生化缺陷。 提高儿童诊断的可靠性 肌张力障碍和某些形式的成人发作的帕金森症应 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.