Regulation and expression of vasopressin-neurophysin II gene.

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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.