Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III
Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III
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DOI：
10.1038/ng1097-171
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发表时间：
1997-10-01
期刊：
影响因子：
30.8
通讯作者：
Lifton, RP
中科院分区：
文献类型：
--
作者：
Simon, DB;Bindra, RS;Lifton, RP
对因食盐浪费引起的遗传性低血钾性碱中毒患者的分析已经证明，这是鉴定肾盐稳态和血压调节的基本要素的肥沃土壤。我们现在证明了这种表型与1号染色体中含有编码肾氯通道基因CLCNKB的一段基因相关联。对该基因的检查显示，功能丧失的突变会损害Henle‘s环粗大的上升支中肾氯的重吸收。已经确定了17个家系的突变，其中包括大片段缺失、无义和错义突变。一些缺失被证明是由于CLCNKB和邻近的相关基因CLCNKA之间的不对等杂交引起的。携带CLCNKB突变的患者的特征是低钾性碱中毒伴盐耗、低血压、正常的镁和高或正常的钙尿症；它们定义了一组不同的Bartter综合征患者，在这些患者中，肾脏没有钙质沉着。这些发现证明了CLCNKB在肾盐重吸收和血压稳态中的关键作用，并证明了特定的CLCNKB拮抗剂作为利尿剂抗高血压药的潜在作用。
Analysis of patients with inherited hypokalaemic alkalosis resulting from salt-wasting has proved fertile ground for identification of essential elements of renal salt homeostasis and blood-pressure regulation. We now demonstrate linkage of this phenotype to a segment of chromosome 1 containing the gene encoding a renal chloride channel, CLCNKB. Examination of this gene reveals loss-of-function mutations that impair renal chloride reabsorption in the thick ascending limb of Henle's loop. Mutations in seventeen kindreds have been identified, and they include large deletions and nonsense and missense mutations. Some of the deletions are shown to have arisen by unequal crossing over between CLCNKB and the nearby related gene, CLCNKA. Patients who harbour CLCNKB mutations are characterized by hypokalaemic alkalosis with salt-wasting, low blood pressure, normal magnesium and hyper-or normocalciuria; they define a distinct subset of patients with Bartter's syndrome in whom nephrocalcinosis is absent. These findings demonstrate the critical role of CLCNKB in renal salt reabsorption and blood-pressure homeostasis, and demonstrate the potential role of specific CLCNKB antagonists as diuretic antihypertensive agents.