M. Ito et al., POSSIBLE INVOLVEMENT OF INEFFICIENT CLEAVAGE OF PREPROVASOPRESSIN BY SIGNAL PEPTIDASE AS A CAUSE FOR FAMILIAL CENTRAL DIABETES-INSIPIDUS, The Journal of clinical investigation, 91(6), 1993, pp. 2565-2571
A transition of G to A at nucleotide position 279 in exon 1 of the vas
opressin gene has been identified in patients with familial central di
abetes insipidus. The mutation predicts an amino acid substitution of
Thr (ACG) for Ala (GCG) at the COOH terminus of the signal peptide in
preprovasopressin (preproVP). Translation in vitro of wild-type and mu
tant mRNAs produced 19-kD preproVPs. When translated in the presence o
f canine pancreatic rough microsomes, wild-type preproVP was converted
to a 21-kD protein, whereas the mutant mRNA produced proteins of 21 k
D and 23 kD. NH2-terminal amino acid sequence analysis revealed that t
he 21-kD proteins from the wild-type and the mutant were proVPs genera
ted by the proteolytic cleavage of the 19-residue signal peptide and t
he addition of carbohydrate. Accordingly, mutant preproVP was cleaved
at the correct site after Thr-19, but the efficiency of cleavage by si
gnal peptidase was < 25% that observed for the wild-type preproVP, res
ulting in the formation of a predominant glycosylated but uncleaved 23
-kD product. These data suggest that inefficient processing of preproV
P produced by the mutant allele is possibly involved in the pathogenes
is of diabetes insipidus in the affected individuals.