Mutant Gene Identification in the Dystonic Rat

肌张力障碍大鼠的突变基因鉴定

• 批准号: 7195769
• 负责人: MARK S LEDOUX
• 金额: $ 19.21万
• 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/7195769
• 关键词: Adult; Affect; Age; American; Amyotrophic Lateral Sclerosis; Animal Model; Arabs; Behavioral; Biochemical; Biological Neural Networks; Brain; Child; Childhood; Childhood Onset Dystonias; Chromosome Pairing; Chromosomes, Human, Pair 7; Classification; Clinic; Complex; Crossbreeding; Cystic Fibrosis; Defect; Development; Disease; Dopa-Responsive Dystonia; Duchenne muscular dystrophy; Dyskinetic syndrome; Dystonia; Essential Tremor; Exhibits; Family; Family member; Female; Fiber; Focal Dystonias; Functional disorder; GTP Cyclohydrolase I; Gene Expression; Generations; Genes; Genetic Transcription; Genotype; Gypsies; Harmaline; Hereditary Dystonia; Heterozygote; Homologous Gene; Homozygote; Human; Huntington Disease; In Situ Hybridization; Inbred Strain; Inferior; Inheritance Patterns; Inherited; Life; Localized; Longevity; Maps; Measures; Minority; Molecular; Motor; Movement; Movement Disorders; Muscle Contraction; Mutation; Myoclonus; Neurology; Neuronal Plasticity; North America; Northern Blotting; Olives - dietary; Output; Parkinson Disease; Partner in relationship; Pathway interactions; Patients; Persons; Phenotype; Physiology; Play; Posture; Primary Dystonias; Protein Truncation; Proteins; Purkinje Cells; Rattus; Relative (related person); Reporting; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Sarcoglycans; Screening procedure; Severities; Site; Sprague-Dawley Rats; Synapses; Syndrome; System; Testing; Time; Tissues; TorsinA; Transcript; Tremor; Ursidae Family; base; cerebellectomy; day; immunocytochemistry; improved; insight; male; mutant; nervous system disorder; neurodevelopment; postnatal; programs; rat genome; relating to nervous system

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。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。人类中存在超过14个与肌张力障碍表型相关的染色体基因座。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。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天内死亡。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空表达。将对肌张力障碍患者进行人类同源物突变筛查。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。