Mutant Gene Identification in the Dystonic Rat

描述（由申请人提供）：肌张力障碍是一种持续肌肉收缩综合征，经常引起扭曲和重复运动，或异常姿势。肌张力障碍是一种比较常见的神经系统疾病。例如，肌张力障碍比亨廷顿病、肌萎缩性侧索硬化症和杜氏肌营养不良症的合并更为普遍。肌张力障碍没有明确的治疗方法，治疗费用昂贵且往往无效。在人类中存在超过14个与肌张力障碍表型相关的染色体位点。然而，迄今为止，只有少数与肌张力障碍的发展明确相关的基因被克隆出来。在人类或动物模型中识别其他缺陷基因应该为肌张力障碍极其复杂的分子和神经网络病理生理学提供关键的见解。此外，任何理解肌张力障碍的努力都可能以重要的方式有助于我们对运动系统和神经元可塑性的理解。

DESCRIPTION (provided by applicant): Dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures. Dystonia is a relatively common neurological disease. For example, dystonia is more prevalent than the combination of Huntington disease, amyotrophic lateral sclerosis and Duchenne muscular dystrophy. There are no definitive cures for dystonia and treatments are expensive and often ineffective. Over fourteen chromosomal loci associated with a dystonia phenotype exist in humans. However, only a few genes clearly associated with the development of dystonia have been cloned to date. Identifying other defective genes in either humans or animal models should provide critical insights into the extremely complex molecular and neural network pathophysiology of dystonia. In addition, any effort to understand dystonia will likely contribute in important ways to our understanding of motor systems and neuronal plasticity. The genetically dystonic (dt) rat, an autosomal recessive mutant discovered in the Sprague-Dawley strain, exhibits a movement disorder that closely resembles the generalized dystonia seen in humans. Dystonic rats demonstrate twisting movements and abnormal postures by Postnatal Day 12. The mutation is fully penetrant. Even with supportive measures, "dt" rats die before 40 days of age. However, cerebellectomy can eliminate dystonia in the "dt" rat, extend its life into adulthood, and enable it to bear and rear offspring. Behavioral, biochemical, and electrophysiological studies indicate that olivocerebellar pathway dysfunction is critical to the dt rat motor syndrome. A systematic approach to finding the mutant gene associated with the dt rat phenotype was begun by crossing homozygote male "dt" rats to females of an inbred strain. The heterozygote first-generation offspring were crossbred to produce second-generation offspring. Rats were genotyped using a set of markers spaced across the rat genome and the responsible gene has been narrowed down to a region of less than 0.5 cM. We plan to locate and clone the mutant gene in the "dt" rat and fully characterize the temporal and spatial expression of this gene's transcriptional and translational products. Patients with dystonia will be screened for mutations in the human homologue. These proposed studies will likely increase our understanding of both dystonia and olivocerebellar motor systems.