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

基本信息

批准号：
10560390
负责人：
Allison Brashear
金额：
$ 63.19万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-10-02 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560390
关键词：
ATP1A3 gene Acceleration 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 Disease Dystonia Dystonia 12 Electronic Health Record Epilepsy Evaluation FDA approved Functional disorder Future Gait Gene therapy trial Genes Genetic Genotype Goals Heat-Shock Response Heterozygote Impairment Individual Intake Ion Transport K ATPase Knowledge Laboratories Laboratory Study Link Magnetic Resonance Imaging Measures Mental disorders Metabolism Missense Mutation Molecular Motor Mutation Natural History Neurologic Neurons Parkinsonian Disorders Pathogenicity Patient Selection Patients Peripheral Nerves Pharmaceutical Preparations 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 blood oxygenation level dependent imaging candidate identification causal variant diagnostic tool disabling disease drug efficacy functional restoration heart rhythm improved infancy interdisciplinary approach molecular sequence database mutant nervous system disorder novel novel diagnostics patient subsets pharmacologic phenotypic data pre-clinical protein function protein misfolding psychologic recruit response risk variant symptom cluster therapy design therapy development trafficking treatment trial

项目摘要

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.

Na/K 泵神经元 α3 亚基 ATP1A3 基因的神经学重要性是其错义突变产生的症状的严重性和范围强调了这一点：运动、认知、该项目采用综合的跨学科方法，包括表型分析。患者对新的表型和机制因素有意见，因为新的表型正在出现。逐步发现，在与相关的数据库中对变异、表型和风险因素进行基因优先搜索临床数据应该加速这一点，因此需要进行实验室测试。致病性和机制，以及FDA批准的药物将进行测试以用于救援。未来临床试验和临床前所需的症状和进展的全面自然史 ATP1A3 存在一系列非同寻常的症状，包括严重的症状。婴儿期表现，但这里的重点是青年和成人中表现的综合症：仍然具有沉重的负担，但也许也对改善生活质量的治疗有更直接的希望。我们发现 ATP1A3 活性受损引起的症状范围很广，包括心脏节律发生，在大脑中，我们发现患有局灶性萎缩的患者和其他仅减少的患者此外，ATP1A3 疾病与许多疾病有重叠。神经系统综合症，包括但不限于自闭症、肌张力障碍、帕金森症、精神疾病，以及我们预计拟议工作的结果还将指出 Na,K-ATP 酶功能障碍如何发生。导致这些更常见的疾病。我们现在的目标是通过加深对 ATP1A3 突变表型多样性和机制的理解来实现治疗，目标如下：目标 1) 扩大 ATP1A3 表型分析的广度和范围，使用诊断工具检测 ATP1A3 相关疾病并测量变化。时间，目标 2) 评估 ATP1A3 突变作为致病因素和危险因素。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特异性，以发现致残疾病 ATP1A3 变体的序列数据库，并将它们与链接的表型数据相关联电子健康记录 (EHR) 或疾病特定表型数据几乎都是 ATP1A3 突变。完全错义和杂合，受损的蛋白质必须存在，从而实现目标 3)：在严格可比的同基因细胞中研究患者的多个突变是否存在蛋白质错误折叠这将检验以下假设：不同的症状群在细胞的反应中具有基础。错误折叠：适应或凋亡对于错误折叠的突变，测试 FDA 批准的和新的错误折叠。从角度来看，纵向表型分析和突变蛋白知识。功能对于选择药理学或基因治疗试验的患者亚组至关重要。

项目成果

期刊论文数量（35）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Research conference summary from the 2014 International Task Force on ATP1A3-Related Disorders.

2014 年 ATP1A3 相关疾病国际工作组研究会议摘要。

DOI：
发表时间：
2017-04
期刊：
影响因子：
0
作者：
Rosewich, Hendrik;Sweney, Matthew T;DeBrosse, Suzanne;Ess, Kevin;Ozelius, Laurie;Andermann, Eva;Andermann, Frederick;Andrasco, Gene;Belgrade, Alice;Brashear, Allison;Ciccodicola, Sharon;Egan, Lynn;George Jr, Alfred L;Lewelt, Aga;Magelby, Jos
通讯作者：
Magelby, Jos

Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.

ATP1A3 相关综合征的心脏表型：一项多中心队列研究。

DOI：
发表时间：
2020
期刊：
影响因子：
9.9
作者：
Balestrini, Simona;Mikati, Mohamad A;Álvarez;Carboni, Michael;Hunanyan, Arsen S;Kherallah, Bassil;McLean, Melissa;Prange, Lyndsey;De Grandis, Elisa;Gagliardi, Alessandra;Pisciotta, Livia;Stagnaro, Michela;Veneselli, Edvige
通讯作者：
Veneselli, Edvige

Mutation in 5' upstream region of GCHI gene causes familial dopa-responsive dystonia.

GCHI 基因 5 上游区域的突变导致家族性多巴反应性肌张力障碍。

DOI：
发表时间：
2011-09
期刊：
影响因子：
0
作者：
Sharma, Nutan;Armata, Ioanna A.;Multhaupt-Buell, Trisha J.;Ozelius, Laurie J.;Xin, Winnie;Sims, Katherine B.
通讯作者：
Sims, Katherine B.

Clinical spectrum of disease associated with ATP1A3 mutations.

与 ATP1A3 突变相关的临床疾病谱。

DOI：
发表时间：
2012-09
期刊：
影响因子：
0
作者：
Ozelius; Laurie J
通讯作者：
Laurie J

Psychiatric disorders in rapid-onset dystonia-parkinsonism.

快速发作的肌张力障碍-帕金森症的精神疾病。

DOI：
发表时间：
2012-09-11
期刊：
影响因子：
9.9
作者：
Brashear, Allison;Cook, Jared F;Hill, Deborah F;Amponsah, Alethea;Snively, Beverly M;Light, Laney;Boggs, Niki;Suerken, Cynthia K;Stacy, Mark;Ozelius, Laurie;Sweadner, Kathleen J;McCall, W Vaughn
通讯作者：
McCall, W Vaughn