GENETIC STUDIES OF LIDDLE'S SYNDROME

肾盐皮质激素敏感性、阿米洛利敏感性上皮细胞 钠通道被认为是净钠重吸收的关键调节器 在人类中，因此是一个强有力的候选人， 有助于高血压的发病机制。我们最近 证明了Liddle综合征，一种常染色体显性形式的人类 高血压，由上皮细胞β亚基突变引起， 钠通道（贝纳克）。迄今为止鉴定的所有突变都引入了 过早终止密码子或移码到基因， 来自编码蛋白质的胞质羧基末端的序列。 临床上，这些突变的后果似乎增加了 在没有盐皮质激素的情况下，通道的活性，允许 增加盐和水的重吸收，导致低肾素 高血压这些发现表明，该通道中的突变 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一补助金，我们建议l）确定 通过对已知的Liddle综合征的研究， 无关的利德尔综合征患者这将决定是否所有 Liddle综合征患者是否存在贝纳克突变， 是遗传异质性。2)确定一组Liddle's患者 综合征使用遗传筛查的风险亲属确定的情况下， 已知的突变。这将允许描述临床 疾病的自然史和自然史。将使用连锁分析 以确定基因遗传对血液的定量影响， 压力，并确定是否在其他因素，如继承 遗传位点有助于表型变异。 Liddle突变的特征证明了先前存在的 未知的途径，通过该途径调节通道活动， study.我们已经开发了一个系统，用于表达突变通道， 以确定这些突变如何改变通道活性。初步 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，2）蛋白质中的序列是什么， 对这种影响负责。

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.