Genetics and biology of a viable mutant mouse with dystonic movements

描述（由申请人提供）：肌张力障碍是一种使人衰弱的临床疾病，其中正常的运动控制被肌肉激活的溢出所破坏。这会导致扭曲的动作和姿势，并对生活质量产生重大影响。最近的工作指出基底神经节，丘脑，皮质和小脑在肌张力障碍中的作用，但关于潜在的机制和途径有不同的理论。传统上，肌张力障碍被认为是一种回路紊乱，意味着神经元放电的异常整合。尽管如此， 许多类型的肌张力障碍是永久性的，并且最近的人脑成像和死后病理学研究表明可能存在结构变化。对于未来的进展，需要一个小鼠模型，将适合药理学，外科手术，生理学（DBS），遗传学测试和干预。携带人类肌张力障碍基因的存活成年小鼠迄今未能表现出肌张力障碍的症状。这使得具有额外病理或注射毒素的突变动物成为迄今为止啮齿动物具有表现出这种疾病的电路的唯一证据。一种新的自发突变小鼠系表现出典型的节段性肌张力障碍的运动和姿势，影响后肢和尾巴，与对立肌肉的共同收缩。这种小鼠具有神经系统突变的不寻常特性，表现出显性遗传，具有高遗传率;成年发病;缺乏失能缺陷;到目前为止，寿命至少为18个月;易于繁殖。虽然症状很严重，但一个关键特征是小鼠能够在轮子上正常行走和奔跑，这些功能主要由脊髓模式发生器和脊髓感觉运动整合介导。这强烈表明损伤是在脊椎上的。遗传图谱发现了两个位点，包括一个修饰基因，并排除了已知的神经突变。核心目标是通过实验确定受影响的基因，建立可量化的trais测试，并测试潜在的病理和机制的初步假设。具体目标1是进行全外显子组测序以鉴定基因。然后将对候选变体进行验证和测试。具体目标2将同时进行，将确定可量化的运动缺陷和电生理学基础，作为治疗工作的基础。具体目标3也将同时进行，将仔细寻找脑、脊髓、外周神经和肌肉中病理或通路激活的证据。这一基本表征计划对于检验小鼠值得广泛用作肌张力障碍模型的假设是必不可少的。该项目是高风险的，因为不确定会发现什么遗传和神经学特征，高回报是因为老鼠的症状一致性，易于繁殖，缺乏特殊的饲养要求将使其成为一个非常实用的工具。

DESCRIPTION (provided by applicant): Dystonia is a debilitating clinical condition in which the normal control of movement is subverted by an overflow of muscle activation. This results in twisting movements and postures, and a major impact on quality of life. Recent work points to roles for the basal ganglia, thalami, cortex and cerebellum in dystonia, but there are different theories about the underlying mechanisms and pathways. Traditionally dystonia has been thought to be a disorder of circuits, meaning aberrant integration of neuronal firing. Nonetheless, many types of dystonia are permanent, and recent human brain imaging and post-mortem pathology studies indicate that there can be structural changes. For future progress a mouse model is needed that would be amenable to pharmacological, surgical, physiological (DBS), and genetic tests and interventions. Viable adult mice carrying human dystonia genes have so far failed to manifest dystonic symptoms. This leaves mutant animals that have additional pathologies, or that were injected with toxins, as the only evidence until now that rodents have circuitry to exhibit the disorder. A new spontaneous mutant mouse line exhibits movements and postures typical of a segmental dystonia affecting hindlimbs and tail, with co-contraction of opposing muscles. The mouse has the unusual properties for a neurological mutation of showing dominant inheritance with high penetrance; adult-onset; a lack of incapacitating deficits; lifespan of at least 18 months so far; and easy breeding. Although the symptoms are severe, a key feature is that the mice are capable of normal walking and running on a wheel, functions that are largely mediated by spinal pattern generators and spinal sensorimotor integration. This strongly suggests that the impairment is supra-spinal. Genetic mapping found two loci including a modifier gene, and ruled out known neurological mutations. The core objectives are to experimentally identify the affected genes, establish tests for quantifiable trais, and test initial hypotheses for underlying pathology and mechanisms. Specific Aim 1 is to do whole exome sequencing to identify the genes. Candidate variants will then be validated and tested. Specific Aim 2, which will be carried out in parallel, will be to determine quantifiable motor deficits and electrophysiological fundamentals as a basis for work on a cure. Specific Aim 3, also to be done in parallel, will be to look carefully for evidence of either pathology or of pathway activation in brain, spinal cord, peripheral nerve, and muscle. This plan of basic characterization is essential to test the hypothesis that the mouse merits wide-spread use as a model of dystonia. The project is high-risk because of uncertainty about what genetic and neurological features will be discovered, and high-reward because the mouse's consistency of symptoms, ease of propagation, and lack of special husbandry requirements will make it a very practical tool.