VASOPRESSIN PROCESSING DEFECTS IN THE BRATTLEBORO RAT - IMPLICATIONS FOR HEREDITARY CENTRAL DIABETES-INSIPIDUS IN HUMANS

The arginine vasopressin (AVP) precursor gene of mammals contains thre e exons encoding the principal domains of the polyprotein precursor, i ncluding vasopressin (exon A), neurophysin (exon B), and glycopeptide (exon C). The AVP precursor (preprohormone) is processed and transport ed through the endoplasmic reticulum (ER), Golgi apparatus, and secret ory vesicles, and finally, mature AVP is secreted from the posterior p ituitary into the circulation. The exact steps of these processes duri ng AVP translation and posttranslation events are not yet well elucida ted. Defects in peptide processing are associated with several genetic disorders, including central diabetes insipidus (CDI). In the Brattle boro rat with CDI, the mRNA and protein of AVP are present in the hypo thalamus, but no circulating AVP is detectable, thus suggesting a proc essing defect, transport defect, or both. The mutated AVP gene precurs or of Brattleboro rat has a deletion of a single base, guanine, in the neurophysin coding region that leads to a frameshift resulting in the loss of the normal stop codon. It has been reported that the mutated precursor is trapped in the ER and does not reach the Golgi apparatus. Recent studies examined AVP secretion in cultured COS cells transfect ed with various constructs from wild-type and mutated Brattleboro AVP gene precursors. The wild-type in vitro studies demonstrated that inta ct neurophysin, but not the glycoprotein coding region, is necessary f or normal AVP processing and secretion. Next, the results demonstrated that the guanine defect in the neurophysin coding region and the prol onged C-terminus accounted for the processing defect in the Brattlebor o rat with CDI. These defects no doubt impair the folding and configur ation necessary for normal processing of the AVP gene precursor in the ER. In hereditary CDI in humans, the majority of the mutations have a lso been shown to occur in the neurophysin coding region. However, in contrast to the recessive defect in the Brattleboro rat, in human CDI, neurotoxicity and denigration of the magnocellular neurons have been observed, and dominant inheritance occurs. Moreover, all mutations are missense, nonsense, or deletions in human CDI rather than the shift i n reading frame and preserved neurons that is observed with the Brattl eboro rat. Thus, the results from studies in the Brattleboro rat may o nly be partially applicable to hereditary CDI in humans.