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: 10031977
• 负责人: Allison Brashear
• 金额: $ 53.68万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-07 至 2021-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10031977
• 关键词: CLINICAL; GENETIC; CELLULAR; CONSEQUENCES; MUTATIONS

 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（由申请人提供）： ATP1A3 基因突变影响大脑中神经元特异性的主要离子转运蛋白、钠泵或 Na,K-ATP 酶，这会导致罕见疾病、儿童交替性偏瘫 (AHC) 和快速偏瘫。发病性肌张力障碍-帕金森症 (RDP) 突变发生在具有显性遗传的家族中，并且在大约 100 个不同的地方发生许多从头突变。该应用的目标是应用高度多学科的协作方法来确定全方位的临床表型；并研究突变的潜在功能，包括运动、认知和发育。和精神症状，预计将通过筛查扩大范围，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 患者表达的全部表型预计与 RDP 患者重叠，并呼吁共享。方法利用先进的大脑成像分析来产生结构和功能特征的特征，可用于三个并行目的：识别受到影响并导致临床症状的特定大脑通路，增强治疗效果。为未来的临床试验提供可用的工具，并通过评估随时间的变化来有效地加强患者的持续护理。路径的识别将有助于未来的治疗设计，例如纵向脑部刺激。研究特别相关，因为 RDP 患者，我们认为AHC 患者可能会出现逐步恶化，通常与压力触发因素有关。第三个组成部分是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。 这是一个关于罕见突变的研究如何促进理解大脑连接（成像）及其与健康（临床表型）和基础科学的关系的例子。 （突变机制）。 1) 确定成人患者 ATP1A3 突变的表型，包括对成人 AHC 患者以及返回和新的 RDP 患者进行筛查，以筛选 AHC 和 RDP 之间缺失的患者群体； 2) 使用先进的成像方法来评估成人 AHC 和 RDP 患者的特定脑通路的改变（与 RDP 神经病理学相关），并对返回的患者启动纵向研究； 3) 检验具有不同酶或细胞后果的突变与相关的假设。临床表型和影像学结果，利用体外诱变和人类细胞培养物中的表达。