Regulation and expression of vasopressin-neurophysin II gene.

在家族性中枢性尿崩症患者中，已发现血管加压素（VP）基因外显子1第279位核苷酸由G变为A。该突变预测在prepro VP中信号肽的COOH-末端由Thr（ACG）取代Ala（GCG）。野生型和突变体mRNA的体外翻译产生19 kDa的prepro VP。当translated在犬胰腺粗微粒体的存在下，野生型prepro VP转化为21 kDa的蛋白质，而突变体mRNA产生的蛋白质的21 kDa和23 kDa。NH_2端氨基酸序列分析表明，野生型和突变型的21 kDa蛋白是由19个信号肽经蛋白酶水解后加入碳水化合物形成的proVP。因此，突变体preproVP在Thr-19后的正确位点被切割，但信号肽酶的切割效率低于野生型preproVP观察到的25%，导致形成主要的糖基化但未切割的23 kDa产物。这些数据表明，由突变等位基因产生的preproVP的低效加工可能参与受影响个体的尿崩症的发病机制。

A transition of G to A at nucleotide position 279 in exon 1 of the vasopressin (VP) gene has been identified in patients with familial central diabetes insipidus. The mutation predicts an amino acid substitution of Thr (ACG) for Ala (GCG) at the COOH-terminus of the signal peptide in prepro VP. Translation in vitro of wild type and mutant mRNAs produced 19 kDa prepro VPs. When traslated in the presence of canine pancreatic rough microsomes, wild type prepro VP was converted to a 21 kDa protein, whereas the mutant mRNA produced proteins of 21 kDa and 23 kDa. NH_2-terminal amino acid sequence analysis revealed that the 21 kDa proteins from the wild type and the mutant were proVPs generated by the proteolytic cleavege of the 19-residue signal peptide and the addition of carbohydrate. Accordingly, mutant preproVP was cleaved at the correct site after Thr-19, but the efficiency of cleavage by signal peptidase was less than 25% that observed for the wild type preproVP, resulting in the formation of a predominant glycosylated but uncleaved 23 kDa product. These data suggest that inefficient processing of preproVP produced by the mutant allele is possibly involved in the pathogenesis of diabetes insipidus in the affected individuals.