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：
7464591
负责人：
Allison Brashear
金额：
$ 66.16万
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/7464591
关键词：
ATP1A3 gene Address Affect Alcohols Biochemical Genetics 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 Rate Reporting Research Personnel Risk Role Signs and Symptoms Single Nucleotide Polymorphism Stress Symptoms Testing Variant Week base clinical phenotype day disabling disease interdisciplinary collaboration 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-帕金森病（RDP）是一种常染色体显性遗传疾病，在数天至数周内突然出现肌张力障碍和帕金森病，随后几乎没有改善。 2004 年，我们报道 RDP 是由 Na,K ATP 酶（ATP1A3 基因）的 a3 亚基突变引起的。 2007年我们公布了10个家庭的数据。在 20 个已知的 RDP 家族中，许多家族在压力、发烧或酗酒后会急性出现永久性肌张力障碍。临床表现与 a3 亚基的已知特性相关。 Na,K-ATP酶通过恢复Na+、K+电化学梯度来转换代谢能量，从而影响神经元活动；谷氨酸和其他递质的再摄取。该提案的前提是，RDP 为了解 ATP1A3 基因在脑功能障碍中的作用提供了一个窗口，并有可能影响原发性肌张力障碍的诊断和治疗。我们假设，与其他遗传性肌张力障碍类似，ATP1A3 突变携带者将出现一系列神经和心理症状，并且 ATP1A3 在更常见的肌张力障碍中发挥作用。一个由具有肌张力障碍（Brashear 博士和 Ozelius 博士）以及 Na,K-ATPase 生物化学和细胞生物学（Sweadner 博士）专业知识的多学科研究人员组成的团队已组建起来，以回答 RDP 中的三个基本问题：（1）什么是完整的ATP1A3突变的表型谱，包括运动和非运动，（2）RDP中的突变谱是什么以及ATP1A3基因作为易感性有何作用（3）使用我们的杂合子 ATP1A3 敲除小鼠作为模型系统，在应激神经元的细胞水平上会发生什么？为了回答这些问题，我们将使用详细的神经学、精神病学和学习评估来明确定义家庭中 RDP 的完整临床表型； ii] 确定 ATP1A3 突变是否涉及更常见的肌张力障碍，这些肌张力障碍具有一些 RDP 特征（喉肌张力障碍、口颌肌张力障碍、音乐家肌张力障碍），以及 iii] 确定生理应激对我们现有杂合子小鼠神经元的影响。拟议的跨机构跨学科合作，包括肌张力障碍和 Na,K-ATP 酶临床、遗传、生化和神经生物学研究的世界专家，将加深我们对这种致残疾病的临床和基础了解。该结果将为了解 Na,K-ATP 酶在神经遗传性疾病中的影响提供一个模型。快速发作的肌张力障碍-帕金森症 (RDP) 具有肌张力障碍和帕金森病的双重特征，这两种神经系统疾病具有运动和神经心理症状，影响了数百万人的生活质量。 RDP 是由 Na K-ATP 酶 (ATP1A3) 的 a3 亚基突变引起的，为了解大脑中 ATP1A3 突变的影响提供了一个窗口。通过定义 ATP1A3 基因突变在人类和我们的小鼠模型中的作用，我们将影响其他神经系统疾病的研究，包括那些具有肌张力障碍、神经心理和精神症状的疾病。