GLU-47, WHICH FORMS A SALT BRIDGE BETWEEN NEUROPHYSIN-II AND ARGININE-VASOPRESSIN, IS DELETED IN PATIENTS WITH FAMILIAL CENTRAL DIABETES-INSIPIDUS

The arginine vasopressin (AVP) gene was sequenced in a pedigree with f amilial central diabetes insipidus (DI). When polymerase chain reactio n-amplified DNAs from affected subjects were subjected to polyacrylami de gel electrophoresis, fragments including exon 2 displayed two addit ional, slower migrating bands. These extra bands represented DNA heter oduplexes, indicating that there was a deletion or insertion mutation in exon 2. As the region with such a mutation was identified by direct sequence analysis, polymerase chain reaction-amplified fragments incl uding the region were subcloned and sequenced. A 3-basepair deletion ( AGG) out of two consecutive AGG sequences (nucleotides 1824-1829) was identified in one of two alleles. The cosegregation of the mutation wi th the DI phenotype in the family was confirmed by restriction enzyme analyses. This mutation should yield an abnormal AVP precursor lacking Glu47 in its neurophysin-II (NP) moiety. Since Glu47 is essential for NP molecules to form a salt bridge with AVP, it is very likely that t he function of NP as a carrier protein for AVP would be impaired. We s uggest that AVP would undergo accelerated proteolytic degradation, and this mechanism would be involved in the pathogenesis of DI in this pe digree.