ISOLATION OF GENE CAUSING DOPA-RESPONSIVE DYSTONIA

肌张力障碍是一种导致非自主肌肉收缩的疾病。多巴- 反应性肌张力障碍(DRD)是一种儿童期起病的特发性肌张力障碍 与其他口吃困难有显著的临床差异。最多的 显著的特点是左旋多巴疗法的“疗效”。DRD是 遗传为常染色体显性遗传，外显性降低。 一些婴儿起病的儿童表现出DRD的临床特征 让人联想到“脑瘫”DRD的基因似乎也是 在某些情况下导致良性的成人晚发型帕金森氏症 有无肌张力障碍史的危险个体。最近在一个DRD家庭中工作 排除了与特发性扭转有关的9q32-q34区域 肌张力障碍，从而证明DRD在基因上与这种疾病不同。 DRD的其他候选基因座也被排除在外。单曲 对DRD脑的病理分析表明，这种疾病是由于 纹状体多巴胺能神经联系发育异常；无退行性 发现了更改。在缺乏其他线索的情况下，我们建议使用位置 克隆以确定导致DRD的基因。我们正在进行联动 利用高信息量对两个DRD大家族的分析 简单序列重复多态(单核苷酸、双核苷酸、三核苷酸和四核苷酸 重复多态)。使用连锁分析，我们排除了65%的 含有导致DRD的突变的基因组。查找链接的标记 将是确定DRD基因的第一步。跟随 我们将创建该地区的高分辨率基因图谱。这 将允许我们最终探索的区域受到限制 物理测绘和克隆技术。然后，我们将应用方法来 从来自该地区的候选人中鉴定DRD基因。 这种基因的识别应该可以更好地诊断儿童霍奇金淋巴瘤 肌张力障碍，并可能使一些儿童免于误诊为 “脑性瘫痪。”最终，对导致DRD的突变的理解 可能为神经的正常发育提供重要的见解 多巴胺能系统。

Dystonia is a disorder causing involuntary muscle contractions. Dopa- responsive dystonia (DRD) is a form of childhood-onset idiopathic dystonia with significant clinical differences from other dystonias. The most significant feature is the "curative" effect of levodopa therapy. DRD is inherited as an autosomal dominant condition with reduced penetrance. Some children with infantile-onset of DRD present clinical features suggestive of "cerebral palsy." The gene for DRD also appears to be responsible for a benign form of late adult onset parkinsonism in some at risk individuals without prior dystonia. Recent work in one DRD family has excluded the 9q32-q34 region implicated in idiopathic torsion dystonia, thus proving that DRD is genetically distinct from this disease. Other candidate loci for DRD have also been excluded. The single pathological analysis of DRD brain suggests that the disorder is due to an abnormal development of striatal dopaminergic connections; no degenerative changes were found. Lacking other clues, we propose to use positional cloning to identify the gene causing DRD. We are performing linkage analysis with two large families with DRD utilizing highly informative simple sequence repeat polymorphisms (mono-, di, tri- and tetranucleotide repeat polymorphisms). Using linkage analysis, we have excluded 65% of the genome as harboring the mutation causing DRD. Finding a linked marker will be the first step towards identifying the gene for DRD. Following linkages we will create a high resolution genetic map of the region. This will allow restriction of the area that we will ultimately explore by physical mapping and cloning techniques. We will then apply methods to identify the DRD gene from among candidates from this region. Identification of this gene should allow better diagnosis in children with dystonia and may spare some children from a misguided diagnosis of "cerebral palsy." Ultimately, an understanding of the mutation causing DRD may provide important insights into normal development of the neural dopaminergic system.