Hochberg Z, Van Lieburg A, Even L, Brenner B, Lanir N, Van Oost B A, Knoers N V
Department of Pediatrics, Rambam Medical Center, Haifa Israel.
J Clin Endocrinol Metab. 1997 Feb;82(2):686-9. doi: 10.1210/jcem.82.2.3781.
Vasopressin V2 receptors, expressed from an x-chromosomal gene, are involved in antidiuresis, but also in release of coagulation factor VIII and von Willebrand factor (vWF). The present study describes autosomal recessive nephrogenic diabetes insipidus (NDI) in a large cluster of patients in Israel's Lower-Galilee. Evidence for an intact V2 receptor was concluded by their normal increase in factor VIII and vWF after desmopressin infusion. Thus, in these patients a defect in the pathway beyond the V2 receptor was suspected. The recent cloning of the human Aquaporin-2 gene enabled us to test this gene as a candidate for such a postreceptor defect. Direct sequencing of the Aquaporin-2 gene revealed a G298T substitution causing a Gly100Stop nonsense mutation in the third transmembrane region. Because this putative disease-causing mutation was identified in index patients of different families, we suggest that all patients are descendants of a common ancestor. Thus, this new entity is characterized by an autosomal recessive NDI. The differential response of clotting factors and urine osmolality to desmopressin may provide a simple tool for clinical diagnosis of a V2-postreceptor defect. The early stop-codon of Aquaporin-2 results in complete resistance to vasopressin antidiuretic effect.
血管加压素V2受体由X染色体基因表达，它不仅参与抗利尿作用，还与凝血因子VIII和血管性血友病因子（vWF）的释放有关。本研究描述了以色列下加利利地区一大群患者中的常染色体隐性遗传性肾性尿崩症（NDI）。通过给予去氨加压素后VIII因子和vWF正常升高，得出V2受体完整的证据。因此，怀疑这些患者存在V2受体下游通路的缺陷。人类水通道蛋白-2基因的近期克隆使我们能够将该基因作为这种受体后缺陷的候选基因进行检测。对水通道蛋白-2基因的直接测序揭示了一个G298T替代，导致在第三个跨膜区域出现Gly100Stop无义突变。由于在不同家族的先证者中都发现了这种假定的致病突变，我们认为所有患者都是同一共同祖先的后代。因此，这个新的病症具有常染色体隐性NDI的特征。凝血因子和尿渗透压对去氨加压素的不同反应可能为V2受体后缺陷的临床诊断提供一个简单工具。水通道蛋白-2的早期终止密码子导致对血管加压素抗利尿作用完全抵抗。
