GENETIC STUDIES OF LIDDLE'S SYNDROME

李德尔氏综合症的遗传学研究

• 批准号: 6302410
• 负责人: RICHARD P LIFTON
• 金额: $ 10.91万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-16 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302410
• 关键词: Xenopus oocyte; autosomal dominant trait; clinical research; electrolyte balance; epithelium; familial hypertension; family genetics; gene mutation; genetic mapping; genetic markers; genotype; human genetic material tag; human population genetics; human subject; hypoaldosteronism; linkage mapping; molecular genetics; phenotype; racial /ethnic difference; renal tubular transport; single strand conformation polymorphism; sodium channel

The renal mineralocorticoid-sensitive, amiloride-sensitive epithelial sodium channel is thought to be a key regulator of net sodium reabsorption in humans, and is consequently a strong candidate to harbor mutations contributing to the pathogenesis of hypertension. We have recently demonstrated that Liddle's syndrome, an autosomal dominant form of human hypertension, results from mutation in the beta subunit of the epithelial sodium channel (bENaC). All mutations identified thus far introduce premature stop codons or frameshifts nto the gene, removing normal sequences from the cytoplasmic carboxy terminus of the encoded protein. Clinically, the consequence of these mutations appears to be increased activity of the channel in the absence of mineralocorticoids, permitting increased salt and water reabsorption and.resulting in a form of low renin hypertension. These findings demonstrate that mutations in this channel can indeed result in human hypertension, and provide a human model of salt-sensitive hypertension. In this grant we propose to l) Determine the spectrum of mutations causing Liddle's syndrome by study of known unrelated subjects with Liddle's syndrome. This will determine whether all patients with Liddle's syndrome have mutations in bENaC or whether there is genetic heterogeneity. 2) Identify a cohort of patients with Liddle's syndrome using genetic screening of at-risk relatives of identified cases with known mutations. This will permit description of the clinical spectrum and natural history of the disease. Linkage analysis will be used to determine the quantitative effects of inheritance of the gene on blood pressure and to determine whether factors such as inheritance at other genetic loci contribute to phenotypic variation. Features of Liddle's mutations demonstrate the existence of a previously unknown pathway by which channel activity is regulated motivating further study. We have developed a system for expression of the mutant channels in order to determine how these mutations alter channel activity. Preliminary evidence demonstrates expression of mutant channels has a marked effect on increasing net channel activity, providing the opportunity to define l) how this effect is mediated and 2) what sequences in the protein are responsible for this effect.

肾盐皮质激素敏感、阿米洛利敏感上皮细胞 钠通道被认为是净钠重吸收的关键调节因子 在人类中，因此是携带突变的有力候选者 有助于高血压的发病机制。我们最近有 证明利德尔氏综合症是人类常染色体显性遗传形式 高血压，是上皮细胞β亚基突变的结果 钠通道（bENaC）。迄今为止发现的所有突变都引入了 过早终止密码子或移码到基因中，消除正常密码子 来自所编码蛋白质的细胞质羧基末端的序列。 临床上，这些突变的后果似乎会增加 在没有盐皮质激素的情况下通道的活性，允许 盐和水的重吸收增加，导致肾素水平降低 高血压。这些发现表明该通道的突变 确实可以导致人类​​高血压，并提供了一个人类模型 盐敏感性高血压。在这笔赠款中，我们建议 l) 确定 通过研究已知的导致利德尔综合征的突变谱 患有利德尔综合症的无关受试者。这将决定是否所有 利德尔综合征患者是否存在 bENaC 突变或是否存在 是遗传异质性。 2) 确定一组利德尔氏症患者 对已确定病例的高危亲属进行基因筛查 具有已知的突变。这将允许描述临床 该疾病的谱和自然史。将使用连锁分析 确定基因遗传对血液的定量影响 压力并确定其他因素（例如遗传）是否 遗传位点导致表型变异。 里德尔突变的特征证明了先前存在 调节通道活动的未知途径进一步激发 学习。我们开发了一种用于表达突变通道的系统 以确定这些突变如何改变通道活性。初步的 有证据表明突变通道的表达对 增加净渠道活动，提供定义 l) 的机会 这种效应是如何介导的以及 2) 蛋白质中的序列是什么 造成这种影响的原因。