MOLECULAR BASIS OF PERIODIC PARALYSES

周期性麻痹的分子基础

• 批准号: 2274233
• 负责人: ERIC P. HOFFMAN
• 金额: $ 34.89万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2274233
• 关键词: autosomal dominant trait; disease /disorder classification; electrophysiology; familial periodic paralysis; genetic regulation; human population genetics; human tissue; hyperkalemias; linkage mapping; membrane structure; molecular cloning; molecular genetics; molecular pathology; muscle disorder diagnosis; muscle function; neuromuscular disorder; nucleic acid probes; polymerase chain reaction; sodium channel; striated muscles; voltage /patch clamp

The Periodic paralyses are dramatic neurological disorders which present as episodic paralysis of most muscle groups of a patient. The paralysis can last from minutes to days. The primary periodic paralyses are genetic disorders which are inherited as autosomal dominant traits. We present convincing preliminary genetic and electrophysiologic evidence that strongly suggests that hyperkalemic periodic paralysis is the result of dominant mutations of the adult skeletal muscle sodium channel alpha-subunit gene, a gene which we have cloned and then mapped to the long arm of human chromosome 17. In this proposal three laboratories have combined their expertise to elucidate the genetic, molecular genetic and electrophysiologic basis for hyperkalemic periodic paralysis. Specifically, we have shown tight linkage between the disease and the sodium channel gene in one extended family (multipoint LOD - 7.02; theta - 0). In addition, electrophysiologic patch-clamp studies of muscle cells from this family have shown specific gating abnormalities of the adult skeletal muscle sodium channel corresponding to the cloned gene. The goal of the research is to test the hypotheses that hyperkalemic periodic paralysis is a genetically homogeneous disorder, that it is caused by mutations of the adult skeletal muscle sodium channel alpha-subunit, and that the molecular genetic abnormalities of the sodium channel gene can be correlated with electrophysiological 'changes of the channel in patient muscle membranes. The proposed research project is a tightly intertwined study divided between laboratories specialized in the molecular biology of neuromuscular disease (Eric Hoffman, PhD), the clinical aspects and cell ,culture of neuromuscular disease (Robert Brown, MD PhD), and the electrophysiology of sodium channels (David Corey, PhD; Stephen Cannon, MD PhD). The proposed research is designed to provide a complete understanding of hyperkalemic periodic paralysis at the molecular level. Identification of both the amino-acid changes of the sodium channel causing paralysis in these patients and the electrophysiologic consequences of these protein abnormalities will give insight into the regulation and function of the skeletal muscle sodium channel in both health and disease.

周期性瘫痪是戏剧性的神经系统 大多数肌肉组的情节瘫痪疾病 病人。 瘫痪可以持续几分钟到几天。 这 原发性周期性瘫痪是遗传疾病 继承为常染色体主导特征。 我们提出了令人信服的初步遗传和 电生理证据强烈表明 高钾血性周期性麻痹是显性突变的结果 成年骨骼肌钠通道α-亚基基因，a 我们已经克隆的基因然后映射到人的长臂 染色体17。在此提案中，三个实验室结合了 他们阐明遗传，分子遗传和的专业知识 高钾血症周期性瘫痪的电生理基础。 具体而言，我们显示了疾病与 一个大家庭中的钠通道基因（多点洛德 - 7.02; theta -0）。 另外，电生理斑块钳 该家族的肌肉细胞的研究显示了特定的门控 成人骨骼肌钠通道异常 对应于克隆基因。 研究的目的是检验假设 高钾血性周期性瘫痪是一种遗传均匀的 疾病，是由成人骨骼突变引起的 肌肉钠通道α-亚基和分子遗传 钠通道基因的异常可以与 电生理学的变化患者肌肉中的通道 膜。 拟议的研究项目是一个紧密交织的 研究在专门从事分子的实验室之间划分 神经肌肉疾病的生物学（Eric Hoffman，PhD），临床 方面和细胞，神经肌肉疾病的培养（罗伯特·布朗， MD博士学位）和钠通道的电生理学（David Corey， 博士学位；斯蒂芬·坎农（Stephen Cannon），医学博士）。 拟议的研究旨在提供完整的 了解分子高血钾周期性瘫痪 等级。 识别钠的氨基酸变化 引起这些患者瘫痪的通道和 这些蛋白质异常的电生理后果将 深入了解骨骼的调节和功能 健康和疾病中的肌肉钠通道。