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: 8886797
• 负责人: Allison Brashear
• 金额: $ 67.73万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886797
• 关键词: ATP1A3 gene; Adolescent; Adult; Affect; Age; Antibiotics; Area; Autopsy; Biochemical; Biological; Biological Neural Networks; Brain; Brain Pathology; Brain imaging; Cell Culture Techniques; Cells; Cerebral Palsy; Childhood; Classification; Clinical; Clinical Trials; Cognitive; Consent; Data; Databases; Deep Brain Stimulation; Defect; Deterioration; Development; Diagnosis; Diagnostic; Diffusion Magnetic Resonance Imaging; Disease; Dystonia 12; Engineering; Enrollment; Evaluation; Family; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Genes; Genetic Recombination; Genotype; Grant; Health; Hemiplegia; Human; Image; Image Analysis; In Vitro; Intervention; Investigation; Ions; Kinetics; Lead; Longitudinal Studies; Magnetic Resonance Imaging; Medical Genetics; Membrane; Methodology; Motor; Movement Disorders; Mutagenesis; Mutation; Na(+)-K(+)-Exchanging ATPase; Neurons; Pathway interactions; Patient Care; Patients; Phenotype; Physiological; Proteins; Protocols documentation; Publishing; Questionnaires; Rare Diseases; Recording of previous events; Recruitment Activity; Reporting; Rest; Science; Severities; Site; Specimen; Stress; Symptoms; Testing; Time; United States National Institutes of Health; Variant; Videotape; age related; base; blood oxygen level dependent; brain pathway; clinical phenotype; cognitive testing; gray matter; imaging biomarker; morphometry; multidisciplinary; neuroimaging; neuropathology; novel; patient population; programs; protein structure; public health relevance; sex; stable cell line; therapy design; therapy development; tool

 DESCRIPTION (provided by applicant): Mutations in the gene ATP1A3 affect the neuron-specific major ion transporter in the brain, the sodium pump or, Na,K-ATPase. This causes rare diseases, Alternating Hemiplegia of Childhood (AHC) and Rapid-Onset Dystonia-Parkinsonism (RDP). Mutations occur in families with dominant inheritance, and there are many de novo mutations occurring in ~100 different places in the gene to date. The objectives of this application are to apply a highly multi-disciplinary, collaborative approach to determine the full range of clinical phenotypes; develop a brain imaging biomarker; and investigate the underlying functionality of the mutations. The full range of clinical phenotypes includes motor, cognitive, developmental, and psychiatric symptoms, and is predicted to expand with a screen to discover patients with new ATP1A3 mutations and features intermediate between AHC and RDP. The full range of phenotypes expressed in adult AHC patients is predicted to overlap with RDP patients and call for a shared approach to therapy development. An advanced brain imaging analysis is hypothesized to lead to a signature of structural and functional features that can be used for three parallel purposes: to identify the specific brain pathways that are impacted and that result in the clinical symptoms, to augment the tools available for future clinical trials, and to potentilly enhance the on-going care of patients by making it possible to evaluate changes over time. The identification of pathways will assist in the future design of treatments, such as deep-brain stimulation. The potential for longitudinal study is particularly relevant because RDP patients, and we think also AHC patients, can have step-wise deterioration, often associated with stressful triggers. The third component, investigation of mutation mechanisms at the biochemical and cell biological level, is needed to determine if specific kinds of mutations result in different phenotypes, and why. This will contribute to rational design of therapies. This is an example of how the study of rare mutations can lead to advances in understanding brain connectivity (imaging) and its relationship to health (clinical phenotypes) and fundamental science (mutation mechanisms). The aims are: 1) Define the phenotypes for ATP1A3 mutation in adult patients including in-depth evaluation of adult AHC patients as well as returning and new RDP patients. Screen for a missing patient population between AHC and RDP; 2) Use advanced imaging methodology to assess alterations of specific brain pathways (correlating with RDP neuropathology) in adult AHC and RDP patients, and initiate longitudinal studies with returning patients; 3) Test the hypothesis that mutations with different enzymatic or cellular consequences will relate to clinical phenotypes and imaging findings, using in vitro mutagenesis and expression in human cell cultures.

 描述(申请人提供)：ATP1A3基因突变会影响大脑中神经元特有的主要离子转运体，即钠泵或Na，K-ATPase。这会导致罕见的疾病，交替出现儿童偏瘫(AHC)和快速发作的肌张力障碍-帕金森综合症(RDP)。突变发生在显性遗传的家族中，到目前为止，在该基因的大约100个不同位置发生了许多从头开始的突变。这项应用的目标是应用高度多学科的协作方法来确定全面的临床表型；开发脑成像生物标记物；并调查突变的潜在功能。全方位的临床表型包括运动、认知、发育和精神症状，预计将随着筛查而扩大，以发现具有新的ATP1A3突变和介于AHC和RDP之间的特征的患者。成人AHC患者表达的各种表型预计与RDP患者重叠，并呼吁采用共同的治疗方法来开发治疗。先进的脑成像分析被假设为导致结构和功能特征的签名，可用于三个平行目的：识别受影响并导致临床症状的特定大脑路径，增加可用于未来临床试验的工具，以及通过使评估随时间变化成为可能，潜在地加强对患者的持续护理。对通路的识别将有助于未来的治疗设计，如脑深部刺激。纵向研究的可能性尤其相关，因为RDP患者，以及我们认为AHC患者，可能会逐步恶化，通常与应激触发因素相关。第三部分，在生化和细胞生物学水平上研究突变机制，以确定是否会导致特定类型的突变。 有不同的表型，以及为什么。这将有助于合理设计治疗方法。这是一个例子，说明对罕见突变的研究如何能够促进对大脑连通性(成像)及其与健康(临床表型)和基础科学(突变机制)的关系的了解。目的是：1)明确成人患者ATP1A3突变的表型，包括对成人AHC患者以及回归和新发RDP患者的深入评估。在AHC和RDP之间筛选失踪患者群体；2)使用先进的成像方法评估成年AHC和RDP患者特定脑通路的变化(与RDP神经病理相关)，并启动与回归患者的纵向研究；3)利用体外突变和在人类细胞培养中的表达，验证具有不同酶或细胞后果的突变将与临床表型和成像结果相关的假设。