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的作用产生抵抗 (AVP)在肾髓质细胞上与水分浓度有关。 临床表现包括严重的多饮多尿，以及 由此产生的严重脱水会导致脑肿胀和死亡。 使用有效的AVP类似物(DDAVP)治疗，在其他形式的DI中有用， 由于终末器官对激素的抵抗，在NDI中无效。 AVP的肾脏作用是通过与V2型受体相连的途径实现的 通过Gs蛋白刺激第二信使cAMP。从理论上讲， 遗传基因缺陷可能位于信号的任何位置 转导途径，但间接证据表明一个可能的受体 叛逃。人类V2受体允许染色体的最新克隆 定位研究表明该受体定位于Xq28， 由家系连锁研究确定的基因缺陷的位置。这 强烈建议，但没有证明受体基因突变是 NDI中的潜在缺陷。我们已经获得了基因组DNA样本 多个患有NDI的家庭，到目前为止有8个家庭 已识别的突变预测会扰乱正常V2的形成 受体。这些发现对我们的研究具有重要的意义 对NDI和正常V2受体发病机制的认识 结构和功能，用于识别受影响的对象和 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 sever 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 determine 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.