CLINICAL, GENETIC, AND CELLULAR CONSEQUENCES OF MUTATIONS IN NA,K-ATPASE ATP1A3

Na/K泵的神经元α 3亚单位ATP 1A 3基因的神经学重要性是 由其错义突变产生的症状的严重性和范围所强调：运动，认知， 和心理上的。该项目采用跨学科综合方法。它包括表型分析， 输入新表型和机械因素的患者。因为新的表型 逐步发现，基因优先搜索数据库中的变异，表型和风险因素， 临床数据应该会加速这一进程。变体需要验证，因此将有实验室测试， 致病性和机制，以及FDA批准的药物将进行抢救测试。其目的是产生 未来临床试验所需的症状和进展的全面自然史，以及临床前 潜在治疗的数据。与ATP 1A 3有一个非凡的症状范围，包括严重的 婴儿的表现，但这里的重点是在青年和成人表现的综合征：仍然有一个 沉重的负担，但也许也有更直接的希望治疗，改善生活质量。 我们发现ATP 1A 3活性受损的症状范围包括心脏 在大脑中，我们发现患者有局灶性萎缩，而其他人只有减少 通过核磁共振成像，有希望恢复功能的代谢。此外，ATP 1A 3疾病与许多疾病重叠， 神经系统综合征，包括但不限于自闭症、肌张力障碍、帕金森综合征、精神疾病，以及 癫痫我们预计，所提出的工作的结果也将指出如何Na，K-ATP酶功能障碍， 导致了这些常见的疾病 我们现在的目标是通过完善我们对ATP 1A 3突变表型多样性和机制的理解来治疗。其目标如下：目的1）扩大ATP 1A 3表型的广度和范围，使用诊断工具检测ATP 1A 3相关疾病并测量随时间的变化， 设计治疗试验所必需的。目的2）评估ATP 1A 3突变作为致病和风险因素 通过使用基因型优先的方法来搜索现有的大量人群和疾病特异性， ATP 1A 3变异体的序列数据库，并将这些与来自连锁的 电子健康记录（EHR）或疾病特异性表型数据。因为ATP 1A 3突变几乎 完全错义和杂合，必须存在受损蛋白，导致目标3）： 在严格可比的同基因细胞中研究来自患者的蛋白质错误折叠的多个突变 线这将检验一个假设，即不同的症状群在细胞对细胞周期的反应中有一个基础。 错误折叠：适应或凋亡。对于确实错误折叠的突变，测试FDA批准的和新的错误折叠 校正药物的功效。从长远来看，纵向表型和突变蛋白的知识， 函数对于选择药理学或基因治疗试验的患者亚组至关重要。

The neurological importance of the gene for the neuronal alpha3 subunit of the Na/K pump, ATP1A3, is underscored by the severity and range of symptoms produced by its missense mutations: motor, cognitive, and psychological. This project uses an integrated interdisciplinary approach. It includes phenotyping on patients with input on new phenotypes and mechanistic factors. Because new phenotypes are being discovered incrementally, a gene-first search for variants, phenotypes and risk factors in databases linked to clinical data should accelerate that. Variants need to be validated, so there will be laboratory tests of pathogenicity and mechanism, and FDA-approved drugs will be tested for rescue. The purpose is to generate a comprehensive natural history of symptoms and progression needed for future clinical trials, and preclinical data for potential treatments. With ATP1A3 there is an extraordinary range of symptoms including severe infantile manifestations, but the focus here is on the syndromes that manifest in youth and adults: still with a heavy burden, but perhaps also with more immediate hope for treatments that improve the quality of life. We have found that the breadth of symptoms from impaired ATP1A3 activity includes cardiac rhythmogenesis, and in the brain, we have found patients with focal atrophy and others with only reduced metabolism by MRI, where there is hope of restoring function. Moreover, ATP1A3 disease overlaps with many neurologic syndromes, including but not limited to autism, dystonia, parkinsonism, psychiatric disease, and epilepsy. We anticipate that the results of the proposed work will also point to how Na,K-ATPase dysfunction contributes to these more common diseases. Our goal now is towards a treatment by refining our understanding of ATP1A3 mutation phenotype diversity and mechanisms. The aims are as follows: Aim 1) Expand the breadth and reach of ATP1A3 phenotyping, using diagnostic tools to detect ATP1A3-related disease and measure changes over time, necessary for designing treatment trials. Aim 2) Assess ATP1A3 mutations as both causative and risk factors for disabling diseases by using a genotype-first approach to search existing large population and disease specific sequence databases for ATP1A3 variants and correlate these with phenotypic data from linked electronic health records (EHR) or disease specific phenotype data. Because ATP1A3 mutations are almost entirely missense and heterozygous, the damaged protein must have to be present, leading to Aim 3): Investigate multiple mutations from patients for protein misfolding in rigorously comparable isogenic cell lines. This will test the hypothesis that different symptom clusters have a basis in the cell’s responses to misfolding: adaptation or apoptosis. For mutations that do misfold, test FDA-approved and new misfolding corrector drugs for efficacy. In perspective, both longitudinal phenotyping and knowledge of mutant protein function will be essential for selecting the patient subgroups for either pharmacologic or gene therapy trials.