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的综合征，经常导致扭曲和重复运动，或异常姿势。肌张力障碍是一种相对常见的神经系统疾病。例如，肌张力障碍几乎是亨廷顿病的十倍。肌张力障碍没有确切的治疗方法，治疗费用昂贵，而且往往无效。迄今为止，已经描述了超过12个与人类肌张力障碍表型相关的染色体基因座。然而，只有三个基因具有明确的因果关系，占主导地位的肌张力障碍表型已被克隆。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重要的见解。此外，任何对肌张力障碍的理解都将有助于我们对运动系统和神经元可塑性的理解。遗传性肌张力障碍（dt）大鼠是在Sprague-Dawley（SD）品系中发现的一种常染色体隐性突变体，表现出与人类中观察到的全身性肌张力障碍非常相似的运动障碍。肌张力障碍大鼠在出生后第12天出现扭转运动和异常姿势。变异是完全渗透性的。即使有支持性措施，dt大鼠也会在40日龄前死亡。然而，小脑切除术可以消除dt大鼠的肌张力障碍，延长其寿命至成年，并使其能够生育后代。行为学、生物化学和电生理学研究表明橄榄小脑通路功能障碍是dt大鼠运动综合征的关键。通过将纯合子雄性dt大鼠与近交系雌性大鼠杂交，开始了寻找与dt大鼠表型相关的突变基因的系统方法。杂合子的第一代后代杂交产生第二代后代。使用一组在大鼠基因组中间隔的标记物对大鼠进行基因分型，并且负责基因已经缩小到小于1 cM的区域。克隆后，该基因转录产物的时空表达将在dt大鼠及其正常同窝仔中进行表征。肌张力障碍患者将被筛查同源人类基因的突变：这些拟议的研究可能会增加我们对肌张力障碍和橄榄小脑运动系统的理解。

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 almost ten-fold more common that Huntington's disease. There are no definitive cures for dystonia and treatments are expensive and often ineffective. Over twelve chromosomal loci associated with a dystonia phenotype in humans have been described to date. However, only three genes with a clear causal relationship to a predominantly dystonic phenotype have been cloned. 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 (SD) 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 1 cM. After cloning, the temporal and spatial expression of this gene's transcription product will be characterized in both dt rats and their normal littermates. Patients with dystonia will be screened for mutations of the homologous human gene: These proposed studies will likely increase our understanding of both dystonia and olivocerebellar motor systems.