GENETIC LINKAGE AND ION CHANNELS IN PERIODIC PARALYSES

周期性麻痹中的遗传连锁和离子通道

• 批准号: 2194408
• 负责人: LOUIS J. PTACEK
• 金额: $ 9.28万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2194408
• 关键词: electromyography; electrophysiology; familial periodic paralysis; family genetics; gene mutation; genetic markers; human genetic material tag; human subject; hyperkalemias; linkage mapping; nucleic acid probes; phenotype; restriction fragment length polymorphism; sodium channel; sodium potassium exchanging ATPase; electromyography; electrophysiology; familial periodic paralysis; family genetics; gene mutation; genetic markers; human genetic material tag; human subject; hyperkalemias; linkage mapping; nucleic acid probes; phenotype; restriction fragment length polymorphism; sodium channel; sodium potassium exchanging ATPase

Hyperkalemic familial periodic paralysis (FPP) is an autosomal dominant muscle disease with onset in infancy or early childhood. This disorder is manifested by transient episodes of paralysis, frequently associated with elevated serum potassium levels. I have obtained a large pedigree containing 40 living individuals affected by hyperkalemic FPP. This family will form the basis for identifying markers linked to this disease. The expected optimal LOD score in this kindred is 18.6. The long term goal of this work is to characterize the gene and its product. Compelling electrophysiologic and biochemical evidence implicates altered sodium regulation as the defect in this disease. It is reasonable to assume that a mutation in a skeletal muscle sodium channel (NaCh) or Na+/K+-ATPase gene is responsible for the disease. I have obtained a human brain NaCh and several Na+/L+-ATPase genes and plan to use them as probes in a linkage study of hyperkalemic FPP. If the disease gene does not co-segregate with one of the candidate genes, a general linkage approach will be used to identify closely linked markers to the disease gene. Additionally, I have obtained a human skeletal muscle cDNA library and will screen it with a human brain NaCh and rat skeletal muscle NaCh genes to isolate additional candidate genes. The second phase of the project will depend on the method with which linkage is established. Co-segregation of a candidate gene with the disease allele will lead to characterization of that gene. If no candidates co-segregate with the disease allele, information from the general linkage will be used to construct a high resolution genetic and physical map. I've also established ties with collaborators who can provide additional pedigrees with the same, and related muscle diseases for further study. This work will lead to prenatal and presymptomatic diagnosis capability. This information may result in better understanding of this disorder, normal muscle development and muscle regulation.

高钾血症家族性周期性瘫痪（FPP）是常染色体显性 肌肉疾病，婴儿期或幼儿期发作。 这种疾病是 表现为瞬态瘫痪发作，经常与 血清钾水平升高。 我获得了一个大的血统 包含40个受高钾血肿影响的活人。 这个家庭 将构成确定与该疾病相关的标记的基础。 这 预期的最佳LOD得分为18.6。 长期目标的 这项工作是为了表征该基因及其产品。 引人入胜的电生理学和生化证据暗示了变化 钠调节作为该疾病的缺陷。 合理的 假设骨骼肌钠通道（NACH）或 Na+/K+-ATPase基因是该疾病的原因。 我已经得到了一个人 脑NACH和几个Na+/L+-ATPase基因，并计划将它们用作探针 在一项高水肿FPP的连锁研究中。 如果疾病基因不 与候选基因之一共隔离，一种一般的联系方法 将用于识别与疾病基因紧密连接的标记。 此外，我获得了人类骨骼肌cDNA库，将 用人脑NACH和大鼠骨骼肌NACH基因筛选它 分离其他候选基因。 项目的第二阶段将取决于该方法 建立了联系。 候选基因共隔离 疾病等位基因将导致该基因的表征。 如果没有 候选人与疾病等位基因共同进行隔离，来自 一般链接将用于构建高分辨率遗传和 物理图。 我还与可以合作者建立了联系 提供其他相同和相关肌肉疾病的血统 进一步研究。 这项工作将导致产前和症状性诊断能力。 这些信息可能会更好地了解这种疾病， 正常的肌肉发育和肌肉调节。