Genetic abnormalities of vasopressin gene and evaluation of gene expression.

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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.