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）：肌张力障碍是一种持续肌肉收缩的综合征，经常引起扭转和重复运动，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病、肌萎缩侧索硬化症和杜氏肌营养不良症的组合更为普遍。肌张力障碍没有明确的治疗方法，而且治疗费用昂贵且通常无效。人类中存在超过十四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生明显相关的基因被克隆。识别人类或动物模型中的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，任何理解肌张力障碍的努力都可能对我们对运动系统和神经元可塑性的理解做出重要贡献。 遗传性肌张力障碍 (dt) 大鼠是在 Sprague-Dawley 品系中发现的一种常染色体隐性突变体，表现出与人类普遍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 天表现出扭曲运动和异常姿势。该突变是完全渗透的。即使采取支持措施，“dt”大鼠也会在 40 天龄之前死亡。然而，小脑切除术可以消除“dt”大鼠的肌张力障碍，将其寿命延长至成年，并使其能够生育和抚养后代。行为、生化和电生理学研究表明，橄榄小脑通路功能障碍对于 dt 大鼠运动综合征至关重要。通过将纯合子雄性“dt”大鼠与近交品系的雌性大鼠杂交，开始了寻找与 dt 大鼠表型相关的突变基因的系统方法。将杂合子第一代后代杂交产生第二代后代。使用一组分布在大鼠基因组中的标记对大鼠进行基因分型，并且相关基因已缩小到小于 0.5 cM 的区域。我们计划在“dt”大鼠中定位并克隆突变基因，并全面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小脑运动系统的理解。