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

NA,K-ATP酶 ATP1A3 突变的临床、遗传和细胞后果

• 批准号: 10297670
• 负责人: Allison Brashear
• 金额: $ 71.71万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297670
• 关键词: ATP1A3 gene; Access to Information; Adult; Anatomy; Apoptosis; Atrophic; Biochemical; Blood flow; Brain; Cardiac; Cell Line; Cells; Clinical; Clinical Data; Clinical Trials; Code; Cognitive; Consensus; Cytoplasm; DNA Sequence Alteration; Data; Data Analyses; Data Set; Databases; Diagnosis; Diagnostic; Disease; Dystonia; Dystonia 12; Electronic Health Record; Epilepsy; Evaluation; FDA approved; Functional disorder; Future; Gait; Gene therapy trial; Genes; Genotype; Goals; Heat-Shock Response; Image; Impairment; Individual; Intake; Ion Transport; Knowledge; Laboratories; Laboratory Study; Link; Magnetic Resonance Imaging; Measures; Medical Genetics; Mental disorders; Metabolism; Missense Mutation; Molecular; Motor; Mutation; Na(+)-K(+)-Exchanging ATPase; Natural History; Neurologic; Neurons; Parkinsonian Disorders; Pathogenicity; Patients; Peripheral Nerves; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Population; Proteins; Publishing; Pump; Quality of life; Records; Risk; Risk Factors; Role; Sampling; Severities; Speech; Structure; Symptoms; Syndrome; Telemedicine; Temperature; Testing; Time; Variant; Work; Youth; afferent nerve; autism spectrum disorder; base; causal variant; disabling disease; drug efficacy; functional restoration; heart rhythm; improved; infancy; interdisciplinary approach; molecular sequence database; mutant; nervous system disorder; novel; novel diagnostics; patient subsets; phenotypic data; pre-clinical; protein function; protein misfolding; psychologic; recruit; response; risk variant; symptom cluster; therapy design; therapy development; tool; trafficking; treatment trial

Summary: 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.

总结：Na/K泵神经元α 3亚基基因的神经学重要性， ATP 1A 3的错义突变所产生的症状的严重性和范围强调了这一点：运动， 认知的和心理的。该项目采用跨学科综合方法。它包括 对患者进行表型分析，并输入新的表型和机械因素。因为新的表型 正在逐渐被发现，基因优先搜索数据库中的变异，表型和风险因素 与临床数据相联系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突变表型的理解来治疗 多样性和机制。目标1）扩展ATP 1A 3的广度和范围 表型分析，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口和疾病， ATP 1A 3变异体的特异性序列数据库，并将这些数据与来自连锁的 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。