Mutant Gene Identification in the Dystonic Rat

肌张力障碍大鼠的突变基因鉴定

• 批准号: 6870753
• 负责人: MARK S LEDOUX
• 金额: $ 20.26万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-05 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870753
• 关键词: animal genetic material tag; clinical research; computational biology; differential display technique; disease /disorder model; dystonia; gene mutation; genetic mapping; genetic markers; genetic screening; genetic transcription; genetic translation; human genetic material tag; human subject; immunocytochemistry; in situ hybridization; laboratory rat; molecular cloning; muscle contraction; neuromuscular disorder; northern blottings; phenotype; polymerase chain reaction; southern blotting

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.

描述（由申请人提供）：肌张力障碍是持续肌肉收缩的综合征，经常引起扭曲和重复运动或异常姿势。肌张力障碍是一种相对常见的神经系统疾病。例如，肌张力障碍比亨廷顿疾病，肌萎缩性侧索硬化症和Duchenne肌营养不良症的结合更为普遍。没有针对肌张力障碍的明确治疗方法，疗法昂贵且常常无效。人类中存在与肌张力障碍表型相关的14个染色体基因座。但是，迄今为止，只有少数几个与肌张力障碍发展有关的基因。在人类或动物模型中识别其他有缺陷的基因应提供对肌张力障碍的极其复杂的分子和神经网络生理学的关键见解。此外，任何了解肌张力障碍的努力都可能以重要的方式为我们对运动系统和神经元可塑性的理解做出贡献。 在Sprague-Dawley菌株中发现的一种常染色体隐性突变体遗传性肌张力蛋白（DT）大鼠表现出一种运动障碍，与人类中看到的广义肌张力障碍非常相似。肌张力大鼠在出生后第12天表现出扭曲运动和异常姿势。突变是完全渗透的。即使采取了支持措施，“ DT”大鼠在40天之前死亡。但是，小脑切除术可以消除“ DT”大鼠中的肌张力障碍，将其寿命延长到成年，并使其能够承受和延伸后代。行为，生化和电生理研究表明，橄榄球途径功能障碍对DT大鼠运动综合征至关重要。通过将纯合子雄性“ DT”大鼠跨到近交菌株的女性开始，从而开始找到与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被杂交以产生第二代后代。使用一组间隔在大鼠基因组上的标记对大鼠进行基因分型，并且负责的基因已缩小到小于0.5 cm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。肌张力障碍患者将在人类同源物中进行突变。这些提出的研究可能会增加我们对肌张力障碍和橄榄球运动系统的理解。