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.

该基因对Na/K泵的神经元α3亚基ATP1A3的神经系统重要性为被其错义突变产生的符号的严重性和范围强调：运动，认知，和心理。该项目采用综合跨学科方法。它包括表型具有新表型和机理因素的输入的患者。因为新表型正在逐步发现，基因优先搜索数据库中的变体，表型和风险因素临床数据应加速。需要验证变体，因此将进行实验室测试致病性和机制以及FDA批准的药物将进行救援。目的是生成未来临床试验所需的症状和进展的全面自然病史和临床前潜在治疗的数据。使用ATP1A3，有多种症状包括严重的症状婴儿表现形式，但这里的重点是在青年和成人中表现出的综合症：仍然重伯恩（Burnen），但也许对改善生活质量的治疗有更直接的希望。我们发现，ATP1A3活动受损的症状广度包括心脏节律发生，在大脑中，我们发现局灶性萎缩患者，其他患者仅降低 MRI的代谢，那里有恢复功能的希望。此外，ATP1A3疾病与许多神经系统综合征，包括但不限于自闭症，肌张力障碍，帕金森氏症，精神病和癫痫。我们预计拟议的工作的结果也将指出Na，K-ATPase功能障碍如何为这些更常见的疾病做出贡献。我们现在的目标是通过完善我们对ATP1A3突变表型多样性和机制的理解来进行治疗。目的如下：目标1）使用诊断工具来检测与ATP1A3相关的疾病，并随时间变化，扩大ATP1A3表型的广度和范围，设计治疗试验所必需的。目标2）评估ATP1A3突变既是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群和特定疾病，用于禁用疾病 ATP1A3变体的序列数据库，并将其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。因为ATP1A3突变几乎是蛋白质受损的蛋白质完全是杂合的，必须存在，导致目标3）：研究患者的多个突变，以在严格可比较的同生细胞中蛋白质折叠率错折叠线。这将检验以下假设：不同症状簇在细胞对错误折叠：适应或凋亡。对于错误折叠的突变，测试FDA批准和新的错误折叠校正药物提高效率。从角度来看，纵向表型和突变蛋白的知识功能对于为药理学或基因治疗试验选择患者亚组至关重要。

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）

Mood and cognition in leucine-rich repeat kinase 2 G2019S Parkinson's disease.

富含亮氨酸重复激酶 2 G2019S 帕金森病的情绪和认知。

DOI：
10.1002/mds.23746
发表时间：
2011
期刊：
Movement disorders : official journal of the Movement Disorder Society
影响因子：
0
作者：
Shanker,Vicki;Groves,Mark;Heiman,Gary;Palmese,Christina;Saunders-Pullman,Rachel;Ozelius,Laurie;Raymond,Deborah;Bressman,Susan
通讯作者：
Bressman,Susan

ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia.

DOI：
10.1111/j.1469-8749.2012.04421.x
发表时间：
2012-11
期刊：
Developmental medicine and child neurology
影响因子：
3.8
作者：
Brashear A;Mink JW;Hill DF;Boggs N;McCall WV;Stacy MA;Snively B;Light LS;Sweadner KJ;Ozelius LJ;Morrison L
通讯作者：
Morrison L

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：
10.1002/mds.23786
发表时间：
2011
期刊：
Movement disorders : official journal of the Movement Disorder Society
影响因子：
0
作者：
Sharma,Nutan;Armata,IoannaA;Multhaupt-Buell,TrishaJ;Ozelius,LaurieJ;Xin,Winnie;Sims,KatherineB
通讯作者：
Sims,KatherineB

De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome.

DOI：
10.1016/j.ymgmr.2018.06.001
发表时间：
2018-09
期刊：
Molecular genetics and metabolism reports
影响因子：
1.9
作者：
Torres A;Brownstein CA;Tembulkar SK;Graber K;Genetti C;Kleiman RJ;Sweadner KJ;Mavros C;Liu KX;Smedemark-Margulies N;Maski K;Yang E;Agrawal PB;Shi J;Beggs AH;D'Angelo E;Lincoln SH;Carroll D;Dedeoglu F;Gahl WA;Biggs CM;Swoboda KJ;Berry GT;Gonzalez-Heydrich J
通讯作者：
Gonzalez-Heydrich J

Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.

DOI：
10.1186/s13023-015-0335-5
发表时间：
2015-09-26
期刊：
Orphanet journal of rare diseases
影响因子：
3.7
作者：
Panagiotakaki E;De Grandis E;Stagnaro M;Heinzen EL;Fons C;Sisodiya S;de Vries B;Goubau C;Weckhuysen S;Kemlink D;Scheffer I;Lesca G;Rabilloud M;Klich A;Ramirez-Camacho A;Ulate-Campos A;Campistol J;Giannotta M;Moutard ML;Doummar D;Hubsch-Bonneaud C;Jaffer F;Cross H;Gurrieri F;Tiziano D;Nevsimalova S;Nicole S;Neville B;van den Maagdenberg AM;Mikati M;Goldstein DB;Vavassori R;Arzimanoglou A;Italian IBAHC Consortium;French AHC Consortium;International AHC Consortium
通讯作者：
International AHC Consortium