Mutant Gene Identification in the Dystonic Rat

描述(申请人提供)：肌张力障碍是一种持续性肌肉收缩综合征，经常导致扭转和重复运动，或不正常的姿势。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、肌萎缩侧索硬化症和杜氏肌营养不良症的组合更普遍。目前还没有确切的治疗肌张力障碍的方法，治疗费用昂贵，而且往往无效。人类存在14个以上与肌张力障碍表型相关的染色体基因座。然而，到目前为止，只克隆了几个与肌张力障碍的发展明显相关的基因。在人类或动物模型中识别其他缺陷基因应该能为肌张力障碍的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，任何了解肌张力障碍的努力都可能在重要方面有助于我们理解运动系统和神经元的可塑性。 遗传性肌张力障碍(DT)大鼠是在Spraogue-Dawley品系中发现的一种常染色体隐性突变，它表现出一种运动障碍，与人类的全身性肌张力障碍非常相似。肌张力障碍大鼠在出生后第12天表现出扭曲的运动和异常的姿势。这种突变是完全穿透的。即使采取了支持性措施，DT大鼠也会在40天前死亡。然而，小脑切除可以消除DT大鼠的肌张力障碍，延长它的寿命到成年期，并使它能够生育和抚养后代。行为学、生化和电生理学研究表明，橄榄球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，开始了一种寻找与DT大鼠表型相关的突变基因的系统方法。将杂合子第一代后代进行杂交，产生第二代后代。使用一组分布在大鼠基因组上的标记对大鼠进行了基因分型，负责的基因已经缩小到不到0.5厘米的区域。我们计划在DT大鼠中定位和克隆突变基因，并充分表征该基因转录和翻译产物的时间和空间表达。肌张力障碍患者将接受人类同源基因突变的筛查。这些拟议的研究可能会增加我们对肌张力障碍和橄榄球小脑运动系统的了解。

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.