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：
7901388
负责人：
Allison Brashear
金额：
$ 62.04万
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 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7901388
关键词：
ATP1A3 gene Address Affect Alcohols Biochemical Biochemistry Biological Models Brain Cell Death Cells Cellular biology Cephalic Characteristics Clinical Data Diagnosis Disease Disease susceptibility Dystonia Dystonia 12 Elements Evaluation Event Family Fever Functional disorder Gene Mutation Genes Genetic Genotype Glutamates Heterozygote Human Impairment Individual Institution K ATPase Knock-out Knockout Mice Larynx Learning Metabolic Metabolic stress Missense Mutation Modeling Motor Mus Mutant Strains Mice Mutation Na(+)-K(+)-Exchanging ATPase Neurobiology Neurologic Neurologic Examination Neurons Other Genetics Parkinson Disease Parkinsonian Disorders Pathology Patients Phenotype Physiological Play Predisposition Primary Dystonias Property Proteins Protocols documentation Publishing Quality of life Reporting Research Personnel Risk Role Signs and Symptoms Single Nucleotide Polymorphism Stress Symptoms Testing Variant base clinical phenotype disabling disease interdisciplinary collaboration meetings member motor impairment mouse model multidisciplinary musician nervous system disorder neurogenetics neuropsychological psychologic reuptake

项目摘要

DESCRIPTION (provided by applicant): Rapid-onset dystonia-parkinsonism (RDP) is an autosomal dominant disease with abrupt onset of dystonia and parkinsonism over days to weeks followed by little improvement. In 2004, we reported that RDP is caused by mutations in the a3 subunit of the Na,K ATPase, the ATP1A3 gene. In 2007 we published data on 10 families. In many of the 20 known RDP families permanent dystonia presents acutely after stress, fever, or alcohol excess. The clinical presentation correlates with known properties of the a3 subunit. The Na,K-ATPase converts metabolic energy by restoring the Na+, K+ electrochemical gradient and as a result impacts neuronal activity; reuptake of glutamate and other transmitters. The premise of this proposal is that RDP provides a window into the role of the ATP1A3 gene in brain dysfunction with the potential to impact the diagnosis and management of primary dystonia. We hypothesize that similar to other genetic dystonias, carriers of the ATP1A3 mutations will have a spectrum of neurologic and psychologic symptoms and that ATP1A3 plays a role in more common dystonias. A multidisciplinary team of investigators with expertise in dystonia (Drs. Brashear and Ozelius) and biochemistry and cell biology of Na,K-ATPase (Dr. Sweadner) has been assembled to answer three essential questions in RDP: (1) what is the full phenotypic spectrum of ATP1A3 mutations, including motor and non-motor, (2) what is the mutational spectrum in RDP and what role does the ATP1A3 gene have as a susceptibility factor in dystonias with characteristics similar to RDP, and (3) what occurs at the cellular level in stressed neurons using our heterozygote ATP1A3 knockout mouse as a model system? To answer these questions we will i] clearly define the full clinical phenotype of RDP in the families using detailed neurologic, psychiatric and learning assessments; ii] determine if ATP1A3 mutations are involved in the more common dystonias that share some of the RDP characteristics (laryngeal, oromandibular, musician's dystonia), and iii] determine the effect of physiologic stress on the neurons in our existing heterozygote mouse. The proposed interdisciplinary collaboration across institutions, of world experts of clinical, genetic, biochemical and neurobiological study of dystonia and Na,K-ATPase, will deepen both our clinical and basic understanding of this disabling disease. The results will provide a model for understanding the impact of Na,K-ATPase in neurogenetic disorders. Rapid-Onset Dystonia-Parkinsonism (RDP) has elements of both dystonia and Parkinson's, two neurologic diseases with motor and neuropsychological symptoms that hinder the quality of life of millions. RDP results from mutations in the a3 subunit of Na K-ATPase (ATP1A3) and provides a window into the affect the ATP1A3 mutations in the brain. By defining the role of the ATP1A3 gene mutations in humans and our mouse model, we will impact the study of other neurological diseases, including those with dystonic, neuropsychological, and psychiatric symptoms.

描述（由申请人提供）：快速发作的肌张力障碍 - 帕金森主义（RDP）是一种常染色体显性疾病，在几天到几周内突然发作，肌张力障碍和帕金森氏症突然发作，随后几乎没有改善。 2004年，我们报道RDP是由Na，K ATPase，ATP1A3基因的A3亚基中突变引起的。 2007年，我们发布了有关10个家庭的数据。在20个已知的RDP家族中，许多人在压力，发烧或饮酒过量后急性表现出急性。临床表现与A3亚基的已知特性相关。 Na，K-ATPase通过恢复Na+，K+电化学梯度来转化代谢能，因此会影响神经元活性。谷氨酸和其他发射机的再摄取。该提案的前提是RDP为ATP1A3基因在脑功能障碍中的作用提供了一个窗口，从而有可能影响原发性肌张力障碍的诊断和管理。我们假设类似于其他遗传肌张力纳斯，ATP1A3突变的载体将具有多种神经系统和心理症状，并且ATP1A3在更常见的肌张力障碍中起作用。一支具有肌张力障碍专业知识（Brashear和Ozelius博士）的研究人员的多学科团队以及Na，K-ATPase（Sweadner博士）的生物化学和细胞生物学已被组装，以回答RDP中的三个基本问题：（1）ATP1A3突变的全部表型，包括Motor的全部表型，包括Motory和Mutnational Motor and Motor and Motor and Motor and Motor and Moter and Moters（2） ATP1A3基因在肌张力障碍中具有类似于RDP的特征的易感因子，并且（3）使用我们的杂合子ATP1A3敲除小鼠作为模型系统，在压力神经元中的细胞水平上发生了什么？为了回答这些问题，我们将使用详细的神经系统，精神病和学习评估来清楚地定义家庭中RDP的完整临床表型； ii]确定具有共同常见的肌张力蛋白的ATP1A3突变是否涉及一些RDP特征（喉，口颌骨，音乐家的肌张力障碍），而III []确定生理应激对我们现有杂合小鼠中神经元的影响。拟议的跨机构的跨学科合作，临床，遗传，生化和神经生物学研究的肌张力障碍和NA，K-ATPase的专家将加深我们对这种残疾疾病的临床和基本理解。结果将为理解Na，K-ATPase在神经遗传疾病中的影响提供模型。快速发作的肌张力障碍 - 帕金森主义（RDP）具有肌张力障碍和帕金森氏症的元素，这是两种具有运动和神经心理学症状的神经系统疾病，妨碍了数百万人的生活质量。 RDP是由Na K-ATPase（ATP1A3）A3亚基的突变引起的，并为影响大脑中的ATP1A3突变提供了一个窗口。通过定义ATP1A3基因突变在人类和我们的小鼠模型中的作用，我们将影响对其他神经系统疾病的研究，包括患有肌张力障碍，神经心理学和精神症状的疾病。