A diabetes insipidus vasopressin prohormone altered outside the central core of neurophysin accumulates in the endoplasmic reticulum

Over 20 mutations affecting the neurophysin moiety of the vasopressin proho rmone, have been identified in families suffering from familial neurohypoph ysial diabetes insipidus (FNDI). Only one of these, NP87E-->stop, is locate d outside the central conserved domain implicated in sorting of the vasopre ssin prohormone. To obtain clues about the mechanism of induction of FNDI b y this atypical mutant we stably expressed wild type and NP87E-->stop vasop ressin prohormones in (neuro)endocrine cell lines. Metabolic labeling and i mmunoprecipitation demonstrated reduced processing of the mutant prohormone to neurophysin. In addition, evoked secretion of neurophysin and vasopress in was diminished, suggesting that part of the mutant is retained in anothe r intracellular compartment than the secretory granules. Indeed, immunofluo rescence demonstrated accumulation of the truncated vasopressin prohormone in the endoplasmic reticulum. We conclude that the presence of the vasopres sin moiety and the central conserved core of the neurophysin domain suffice s for sorting and processing, but not for efficient endoplasmic reticulum e xit of the vasopressin-neurophysin molecule. (C) 2000 Elsevier Science Irel and Ltd. All rights reserved.