STUDIES ON NEPHROGENIC DIABETES INSIPIDUS

肾源性尿崩症(NDI)是一种遗传性X连锁疾病 受影响的受试者对加压素(AVP)的作用有抵抗力 在肾髓质细胞上负责水分的浓缩。临床 表现为严重的多饮和多尿，以及由此产生的 严重脱水会导致脑肿胀和死亡。通过以下方式治疗 有效的AVP类似物(DDAVP)在其他形式的DI中有用，但无效 由于终末器官对激素的抵抗力而导致的NDI。肾脏的作用 AVP通过Gs蛋白连接的V2型受体介导 去刺激第二信使营。从理论上讲，遗传基因 缺陷可能位于信号转导路径上的任何位置，但是 间接证据表明可能存在受体缺陷。最新的克隆 人类V2受体允许的染色体定位研究 结果表明，该受体定位于基因缺陷部位Xq28 由家庭关联研究确定的。这强烈地表明了这一点，但确实如此 不能证明受体基因突变是NDI的潜在缺陷。 我们已经获得了多个NDI家系的基因组DNA样本，在 到目前为止，已有8个家庭发现了预测会扰乱 形成正常的V2受体。这些发现具有重要的意义 对我们理解新城疫和新城疫发病机制的启示 正常的V2受体结构和功能，用于识别受影响的人 受试者和携带者，并最终用于疾病的基因治疗。

Nephrogenic diabetes insipidus (NDI) is an inherited X-linked disorder in which affected subjects are resistant to the actions of vasopressin (AVP) on renal medullary cells responsible for water concentration. Clinical manifestations include severe polydipsia and polyuria, and resultant severe dehydration can lead to cerebral swelling and death. Treatment with a potent AVP analog (DDAVP), useful in other forms of DI, is ineffective in NDI because of end-organ resistance to the hormone. The renal actions of AVP are mediated through a V2 type receptor linked via the Gs protein to stimulation of the 2nd messenger cAMP. In theory, the inherited gene defect could be located anywhere along the signal transduction path, but indirect evidence suggested a likely receptor defect. The recent cloning of a human V2 receptor permitted chromosomal localization studies which showed that the receptor is localized to Xq28, the site of the gene defect as determined by family linkage studies. This strongly suggested but did not prove that a receptor gene mutation is the underlying defect in NDI. We have obtained genomic DNA samples on multiple families with NDI, and in eight families thus far have identified mutations predicted to disrupt formation of a normal V2 receptor. These findings have important implications for our understanding of the pathogenesis of NDI and of normal V2 receptor structure and function, for identification of affected subjects and carriers, and eventually for gene therapy of the disease.