Clinical, Genetic, And Cellular Consequences of Mutations in Na,K-ATPase ATP1A3

描述(申请人提供)：快速发作的肌张力障碍-帕金森综合症(RDP)是一种常染色体显性疾病，突然发作肌张力障碍和帕金森综合症，持续数天至数周，随后几乎没有改善。2004年，我们报道了RDP是由Na，K-ATPase，ATP1A3基因的A3亚基突变引起的。2007年，我们公布了10个家庭的数据。在已知的20个RDP家族中，许多人在压力、发烧或酗酒后出现永久性肌张力障碍。临床表现与A3亚基的已知特性相关。Na，K-ATPase通过恢复Na，K电化学梯度来转换代谢能量，从而影响神经元的活动，重新摄取谷氨酸和其他递质。这项建议的前提是RDP提供了一个窗口，了解ATP1A3基因在脑功能障碍中的作用，并有可能影响原发性肌张力障碍的诊断和治疗。我们假设，与其他遗传性肌张力障碍类似，ATP1A3突变的携带者将会有一系列神经和心理症状，ATP1A3在更常见的肌张力障碍中发挥作用。一个多学科的研究团队，在肌张力障碍(Brasshire和Ozelius博士)以及Na，K-ATPase的生物化学和细胞生物学(Dr.Sweadner)方面具有专长，以回答RDP中的三个基本问题：(1)ATP1A3突变的完整表型谱是什么，包括运动和非运动，(2)RDP的突变谱是什么，ATP1A3基因作为与RDP相似的特征的易感因素在肌张力障碍中具有什么作用，以及(3)使用我们的杂合子ATP1A3基因敲除小鼠作为模型系统，应激神经细胞水平上发生了什么？为了回答这些问题，我们将：1)使用详细的神经学、精神病学和学习评估来清楚地定义RDP家族中的完整临床表型；ii)确定ATP1A3突变是否与更常见的肌张力障碍有关(喉部、口颌、音乐家肌张力障碍)，以及iii)确定生理应激对我们现有的杂合子小鼠神经元的影响。拟议的跨机构跨学科合作，由世界上研究肌张力障碍和Na，K-ATPase的临床、遗传、生化和神经生物学专家组成，将加深我们对这种致残性疾病的临床和基本理解。这一结果将为理解Na，K-ATPase在神经遗传性疾病中的影响提供一个模型。 快速发作的肌张力障碍-帕金森氏症(RDP)同时具有肌张力障碍和帕金森氏症的元素，这两种神经疾病具有运动和神经心理症状，阻碍了数百万人的生活质量。RDP是由Na K-ATPase(ATP1A3)的A3亚单位突变引起的，它为研究大脑中ATP1A3突变的影响提供了一个窗口。通过确定ATP1A3基因突变在人类和我们的小鼠模型中的作用，我们将影响其他神经疾病的研究，包括那些具有肌张力障碍、神经心理和精神症状的疾病。

DESCRIPTION (provided by applicant): Rapid-onset dystonia-parkinsonism (RDP) is an autosomal dominant disease with abrupt onset of dystonia and parkinsonism over days to weeks followed by little improvement. In 2004, we reported that RDP is caused by mutations in the a3 subunit of the Na,K ATPase, the ATP1A3 gene. In 2007 we published data on 10 families. In many of the 20 known RDP families permanent dystonia presents acutely after stress, fever, or alcohol excess. The clinical presentation correlates with known properties of the a3 subunit. The Na,K-ATPase converts metabolic energy by restoring the Na+, K+ electrochemical gradient and as a result impacts neuronal activity; reuptake of glutamate and other transmitters. The premise of this proposal is that RDP provides a window into the role of the ATP1A3 gene in brain dysfunction with the potential to impact the diagnosis and management of primary dystonia. We hypothesize that similar to other genetic dystonias, carriers of the ATP1A3 mutations will have a spectrum of neurologic and psychologic symptoms and that ATP1A3 plays a role in more common dystonias. A multidisciplinary team of investigators with expertise in dystonia (Drs. Brashear and Ozelius) and biochemistry and cell biology of Na,K-ATPase (Dr. Sweadner) has been assembled to answer three essential questions in RDP: (1) what is the full phenotypic spectrum of ATP1A3 mutations, including motor and non-motor, (2) what is the mutational spectrum in RDP and what role does the ATP1A3 gene have as a susceptibility factor in dystonias with characteristics similar to RDP, and (3) what occurs at the cellular level in stressed neurons using our heterozygote ATP1A3 knockout mouse as a model system? To answer these questions we will i] clearly define the full clinical phenotype of RDP in the families using detailed neurologic, psychiatric and learning assessments; ii] determine if ATP1A3 mutations are involved in the more common dystonias that share some of the RDP characteristics (laryngeal, oromandibular, musician's dystonia), and iii] determine the effect of physiologic stress on the neurons in our existing heterozygote mouse. The proposed interdisciplinary collaboration across institutions, of world experts of clinical, genetic, biochemical and neurobiological study of dystonia and Na,K-ATPase, will deepen both our clinical and basic understanding of this disabling disease. The results will provide a model for understanding the impact of Na,K-ATPase in neurogenetic disorders. Rapid-Onset Dystonia-Parkinsonism (RDP) has elements of both dystonia and Parkinson's, two neurologic diseases with motor and neuropsychological symptoms that hinder the quality of life of millions. RDP results from mutations in the a3 subunit of Na K-ATPase (ATP1A3) and provides a window into the affect the ATP1A3 mutations in the brain. By defining the role of the ATP1A3 gene mutations in humans and our mouse model, we will impact the study of other neurological diseases, including those with dystonic, neuropsychological, and psychiatric symptoms.