Possible involvement of inefficient cleavage of preprovasopressin by signal peptidase as a cause for familial central diabetes insipidus.

A transition of G to A at nucleotide position 279 in exon 1 of the vasopressin
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 preprovasopression (preproVP).
Translation in vitro of wild-type and mutant mRNAs produced 19-kD preproVPs. When
translated in the presence of canine pancreatic rough microsomes, wild-type
preproVP was converted to a 21-kD protein, whereas the mutant mRNA produced
proteins of 21 kD and 23 kD. NH2-terminal amino acid sequence analysis revealed
that the 21-kD proteins from the wild-type and the mutants were proVPs generated
by the proteolytic cleavage 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 < 25% that
observed for the wild-type preproVP, resulting in the formation of a predominant
glycosylated but uncleaved 23-kD 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.