GENETIC STUDIES OF LIDDLE'S SYNDROME

肾皮质激素敏感、阿米洛利敏感的肾上皮细胞 钠通道被认为是钠净重吸收的关键调节因素。 在人类中，因此是隐藏突变的有力候选者 参与了高血压的发病机制。我们最近做了 证明了利德尔综合征，人类的一种常染色体显性形式 高血压，由上皮细胞β亚单位突变所致 钠通道(贝那克)。到目前为止发现的所有突变都会导致 过早终止基因的密码子或移码，去除正常 编码蛋白质胞质羧基末端的序列。 临床上，这些突变的后果似乎是增加的。 在没有糖皮质激素的情况下，通道的活动 增加盐和水的重吸收，导致肾素降低 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 盐敏性高血压。在这笔赠款中，我们向L提议)确定 通过研究已知的基因突变导致利德尔综合征的谱 与利德尔综合征无关的研究对象。这将决定是否所有 利德尔综合征患者是否存在苯丙氨酸基因突变 是遗传异质性。2)确定利德尔病患者的队列 对确诊病例的高危亲属进行基因筛查的综合征 已知的基因突变。这将允许描述临床 疾病的谱系和自然病史。将使用连锁分析 确定基因遗传对血液的数量效应 压力，并确定其他因素，如遗传是否 遗传基因座对表型变异有贡献。 利德尔突变的特征证明了以前 调节通道活动的未知途径进一步激励 学习。我们已经开发了一种表达突变通道的系统 以确定这些突变如何改变通道活动。初步 证据表明突变通道的表达对 增加网络渠道活跃度，提供定义L的机会) 这种效应是如何介导的，以及2)蛋白质中的哪些序列 对这一影响负有责任。

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.