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J Biol Chem, Vol. 274, Issue 27, 18965-18972, July 2, 1999

Mechanism of Endoplasmic Reticulum Retention of Mutant Vasopressin Precursor Caused by a Signal Peptide Truncation Associated with Diabetes Insipidus

Nicole BeuretDagger , Jonas Rutishauser, Marc D. BiderDagger , and Martin SpiessDagger

From the Dagger  Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland and  Department of Medicine, Kantonsspital, CH-6000 Luzern 16, Switzerland

Autosomal dominant neurohypophyseal diabetes insipidus is caused by mutations in the gene encoding the vasopressin precursor protein, prepro-vasopressin-neurophysin II. We analyzed the molecular consequences of a mutation (Delta G227) recently identified in a Swiss kindred that destroys the translation initiation codon. In COS-7 cells transfected with the mutant cDNA, translation was found to initiate at an alternative ATG, producing a truncated signal sequence that was functional for targeting and translocation but was not cleaved by signal peptidase. The mutant precursor was completely retained within the endoplasmic reticulum. The uncleaved signal did not affect folding of the neurophysin portion of the precursor, as determined by its protease resistance. However, formation of disulfide-linked aggregates indicated that it interfered with the formation of the disulfide bond in vasopressin, most likely by blocking its insertion into the hormone binding site of neurophysin. Preventing disulfide formation in the vasopressin nonapeptide by mutation of cysteine 6 to serine was shown to be sufficient to cause aggregation and retention. These results indicate that the Delta G227 mutation induces translation of a truncated signal sequence that cannot be cleaved but prevents correct folding and oxidation of vasopressin, thereby causing precursor aggregation and retention in the endoplasmic reticulum.


Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.



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