ISOLATION OF GENE CAUSING DOPA-RESPONSIVE DYSTONIA

肌张力障碍是一种引起不自主肌肉收缩的疾病。 多巴- 反应性肌张力障碍（DRD）是一种儿童期发作的特发性肌张力障碍 与其他肌张力障碍有显著的临床差异。最 显著的特征是左旋多巴疗法的"治疗"效果。 DRD是 作为一种常染色体显性遗传的疾病，遗传率降低。 部分DRD患儿起病急， 提示"脑瘫"。"DRD的基因似乎也 在某些人中， 没有先前肌张力障碍的风险个体。 DRD家族的最新研究 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在遗传上与这种疾病不同。 DRD的其他候选基因座也已被排除。 单 DRD脑的病理分析表明，这种疾病是由于 纹状体多巴胺能连接发育异常;无退行性 由于缺乏其他线索，我们建议使用位置 克隆以鉴定引起DRD的基因。我们正在执行连接 利用高信息量对两个DRD大家族进行分析 简单序列重复多态性（单、双、三和四核苷酸 重复多态性）。 使用连锁分析，我们排除了65%的 基因组携带导致DRD的突变 查找链接的标记 将是确定DRD基因的第一步。 以下 我们将建立该地区的高分辨率遗传图谱。 这 将允许限制我们最终将探索的区域， 物理映射和克隆技术。 然后，我们将应用方法来 从该区域的候选者中鉴定DRD基因。 该基因的鉴定将有助于更好地诊断儿童 肌张力障碍，并可能使一些儿童免于被误导的诊断， "脑瘫。"最终，对导致DRD的突变的理解 可能为神经系统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.