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：
9033953
负责人：
Allison Brashear
金额：
$ 59.37万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/9033953
关键词：
ATP1A3 gene Adolescent Adult Affect Age Antibiotics Area Assessment tool 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 Thinking 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 patient subsets programs protein structure psychiatric symptom sex stable cell line therapy design therapy development tool

项目摘要

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（通过应用程序提供）：基因ATP1A3中的突变会影响大脑，钠泵或Na，K-ATPase中神经特异性的主要离子转运蛋白。这会引起罕见的疾病，交替的儿童偏瘫（AHC）和快速发作的肌张力障碍症（RDP）。突变发生在具有主导性遗传的家庭中，迄今为止，基因中约有100个不同的地方发生了许多从头突变。本应用程序的目标是采用高度多学科的协作方法来确定临床表型的全部范围。开发脑成像生物标志物；并研究突变的潜在功能。临床表型的全部范围包括运动，认知，发育和精神病症状，预计会随着筛查而扩展，以发现具有新的ATP1A3突变的患者，并在AHC和RDP之间进行了中间的特征。预计在成年AHC患者中表达的全范围表型将与RDP患者重叠，并呼吁采用共同的治疗方法开发。假设先进的大脑成像分析可导致结构和功能功能的特征签名，这些特征可用于三个平行目的：确定受影响的特定大脑途径并导致临床症状，以增强未来临床试验可用的工具，并通过使患者的持续增强患者的持续护理进行评估，从而可以评估时间的变化。识别途径将有助于未来的治疗设计，例如深脑刺激。纵向研究的潜力尤其重要，因为RDP患者及我们也认为AHC患者可以具有逐步确定，通常与压力大的触发器有关。第三个成分是对生化和细胞生物学水平上突变机制的研究，以确定特定种类的突变是否结果在不同的表型中，原因。这将有助于疗法的理性设计。这是一个罕见突变的研究如何导致理解大脑连通性（成像）及其与健康（临床表型）和基本科学（突变机制）的关系的一个例子。目的是：1）定义成年患者ATP1A3突变的表型，包括对成人AHC患者的深入评估以及返回和新的RDP患者。筛选AHC和RDP之间缺失的患者人群； 2）使用先进的成像方法来评估成人AHC和RDP患者特定脑途径（与RDP神经病理学相关）的变化，并开始对返回患者进行纵向研究； 3）检验以下假设：具有不同酶促或细胞后果的突变将与人类细胞培养物中的体外诱变和表达有关临床表型和成像发现有关。