STUDIES ON NEPHROGENIC DIABETES INSIDIPUS

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， 肾脏髓质细胞负责水的浓缩。 临床 临床表现包括严重的多饮和多尿， 脱水会导致脑肿胀和死亡。 的治疗 有效的AVP类似物（DDAVP），在其他形式的DI中有用，在 NDI是由于终末器官对激素的抵抗。 肾的作用 AVP是通过V2型受体介导的，V2型受体通过Gs蛋白连接到 第二信使cAMP的刺激。 理论上，遗传基因 缺陷可以位于信号转导通路的任何沿着，但 间接证据表明可能存在受体缺陷。 最近的克隆 的人V2受体允许染色体定位研究， 结果表明，该受体定位于Xq28，即基因缺陷的位点 这是由家庭联系研究确定的。 这强烈地暗示， 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家庭的基因组DNA样本， 迄今为止，一个家族已经确定了一种突变， 正常V2受体的形成。 这些发现具有重要 对我们理解NDI和正常人的发病机制的影响 V2受体结构和功能，用于识别受影响的受试者 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 one family thus far have identified a mutation 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.