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: 8055282
• 负责人: Allison Brashear
• 金额: $ 61.9万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055282
• 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

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（由申请方提供）：速发型肌张力障碍-帕金森综合征（RDP）是一种常染色体显性遗传疾病，在数天至数周内突然发作肌张力障碍和帕金森综合征，随后几乎没有改善。2004年，我们报道了RDP是由Na，K ATP酶的α 3亚基（ATP 1A 3基因）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，许多家族在应激、发热或酒精过量后急性出现永久性肌张力障碍。临床表现与α 3亚基的已知特性相关。Na，K-ATP酶通过恢复Na+，K+电化学梯度转换代谢能量，从而影响神经元活动;谷氨酸和其他递质的再摄取。该建议的前提是，RDP提供了一个窗口，以了解ATP 1A 3基因在脑功能障碍中的作用，并有可能影响原发性肌张力障碍的诊断和管理。我们假设，类似于其他遗传性肌张力障碍，ATP 1A 3突变的携带者将有一系列的神经和心理症状，ATP 1A 3在更常见的肌张力障碍中发挥作用。具有肌张力障碍专业知识的多学科研究团队（Brashear和Ozelius博士）以及Na，K-ATPase的生物化学和细胞生物学（斯韦德纳博士）已经聚集在一起回答RDP中的三个基本问题：（1）ATP 1A 3突变的完整表型谱是什么，包括运动型和非运动型，（2）RDP的突变谱是什么，ATP 1A 3基因作为具有与RDP相似特征的肌张力障碍的易感因子具有什么作用，以及（3）以我们的杂合子ATP 1A 3基因敲除小鼠为模型系统，在应激神经元的细胞水平上发生了什么？为了回答这些问题，我们将i）使用详细的神经病学、精神病学和学习评估来清楚地定义家族中RDP的完整临床表型; ii）确定ATP 1A 3突变是否涉及共享一些RDP特征的更常见的肌张力障碍（喉肌张力障碍、口下颌肌张力障碍、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中的神经元的影响。拟议的跨机构跨学科合作，包括肌张力障碍和Na，K-ATP酶的临床，遗传，生物化学和神经生物学研究的世界专家，将加深我们对这种致残性疾病的临床和基本理解。该结果将为了解Na，K-ATP酶在神经遗传性疾病中的作用提供一个模型。 快速发作的肌张力障碍-帕金森综合征（RDP）具有肌张力障碍和帕金森病的元素，这两种神经系统疾病具有运动和神经心理症状，阻碍了数百万人的生活质量。RDP由Na K-ATP酶（ATP 1A 3）的α 3亚基突变引起，并提供了一个了解ATP 1A 3突变对大脑影响的窗口。通过定义ATP 1A 3基因突变在人类和小鼠模型中的作用，我们将影响其他神经系统疾病的研究，包括那些具有张力障碍，神经心理和精神症状的疾病。