Genetic abnormalities of vasopressin gene and evaluation of gene expression.

家族性中枢性尿囊症（FDI）是一种常染色体显性遗传病，由精氨酸抗利尿素（AVP）缺乏引起。我们之前报道了日本FDI患者信号肽区（A-1T）和神经生理区（E47del, G57S,G62W,G65V,C67stop）中编码AVP前体的AVP基因中的6个不同突变。为了研究FDI的发病机制，我们用野生型或突变型人AVP cDNA转染小鼠促皮质细胞AtT20。瞬时转染研究表明，与野生型相比，转染每种突变AVP cDNA的细胞在培养基中的AVP免疫反应性显著降低（2 - 30%）。在AVP基因杂合的患者中，可以预期正常等位基因产生的AVP足以预防尿崩症。然而，该病以常染色体显性方式表现。这表明突变的AVP基因产物可能影响野生型前体的AVP分泌。在共转染实验中检测了潜在的显性负作用。然而，在AtT20细胞中短暂共转染野生型和突变型AVP cdna的培养基中，AVP免疫活性没有改变。进一步的研究将是必要的，以解释sutosomal显性性质的疾病。

Familial central diabetes insipidus (FDI) is an autosomal dominant disease caused by a deficiency of arginine vasopressin (AVP). We have previously reported 6 distinct mutations within the AVP gene encoding the AVP precursor in Japanese patients with FDI in the signal peptide region (A-1T), and the neurophysin region (E47del, G57S,G62W,G65V,C67stop). To study the pathogenesis of FDI,mouse corticotroph AtT20 cells were transfected with either wild-type or mutant human AVP cDNA.Transient transfection studies showed that the AVP immunoreactivity in culture media from cells transfected with each mutant AVP cDNA was markedly decreased compared to wild type (2 to 30%). In patients with AVP gene heterozygosity, one would expect AVP production from the normal allele to be sufficient in preventing diabetes insipidus. However, the disease manifests itself in an autosomal dominant manner. This suggestes that mutant AVP gene products may affect AVP secretion from the wild-type precursor. The potential dominant negative effect was examined in cotransfection experiments. However, the AVP immunoactivity in media obtained from AtT20 cells transiently co-transfected with wild-type and mutant AVP cDNAs was not altered. Further studies will be necessary to explain the sutosomal dominant nature of this disease.