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

 描述（由申请方提供）：基因ATP 1A 3突变影响脑中神经元特异性主要离子转运蛋白、钠泵或Na，K-ATP酶。这会导致罕见的疾病，儿童交替性偏瘫（AHC）和快速发作的肌张力障碍-帕金森综合征（RDP）。突变发生在显性遗传的家族中，迄今为止，在基因的约100个不同位置发生了许多从头突变。本申请的目的是应用高度多学科的协作方法来确定全范围的临床表型;开发脑成像生物标志物;并研究突变的潜在功能。全范围的临床表型包括运动，认知，发育和精神症状，并预计将扩大与屏幕，以发现新的ATP 1A 3突变和AHC和RDP之间的中间特征的患者。预计成人AHC患者表达的全系列表型与RDP患者重叠，并需要共同的治疗方法。假设先进的脑成像分析导致结构和功能特征的签名，可用于三个并行目的：识别受影响并导致临床症状的特定脑通路，增加可用于未来临床试验的工具，并通过评估随时间推移的变化来潜在地增强患者的持续护理。对通路的识别将有助于未来治疗方法的设计，例如脑深部电刺激。纵向研究的潜力是特别相关的，因为RDP患者，我们认为也AHC患者，可以有逐步恶化，往往与压力触发。第三个组成部分是在生物化学和细胞生物学水平上调查突变机制，以确定是否导致特定类型的突变。 在不同的表型中，以及为什么。这将有助于合理设计治疗方案。这是一个例子，说明罕见突变的研究如何能够促进对大脑连接（成像）及其与健康（临床表型）和基础科学（突变机制）的关系的理解。其目标是：1）定义成人患者中ATP 1A 3突变的表型，包括对成人AHC患者以及返回和新的RDP患者的深入评估。筛查AHC和RDP之间的缺失患者人群; 2）使用先进的成像方法评估特定脑通路的改变（与RDP神经病理学相关），并开始对返回患者进行纵向研究; 3）检验具有不同酶或细胞后果的突变将与临床表型和成像发现相关的假设，使用体外诱变和在人细胞培养物中表达。

 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.