V2 vasopressin receptor dysfunction in nephrogenic diabetes insipidus caused by different molecular mechanisms

Hum Mutat. 1998;12(3):196-205. doi: 10.1002/(SICI)1098-1004(1998)12:3<196::AID-HUMU7>3.0.CO;2-F.


Loss-of-function mutations in the V2 vasopressin receptor (AVPR2) gene have been identified as a molecular basis for X-linked nephrogenic diabetes insipidus (NDI). Herein, we describe a novel deletion mutation at nucleotide position 102 (delG102) found in a Russian family resulting in a frameshift and a truncated receptor protein. Furthermore, we analyzed the AVPR2 gene of two other unrelated boys with NDI from our patient clientele. These patients showed previously described mutations (R137H, R181C). In-depth characterization of the three mutant AVPR2s by a combination of functional and immunological techniques permitted further insight into molecular mechanisms leading to receptor dysfunction. Premature truncation of the AVPR2 (delG102) led to a drastically reduced receptor protein expression in transfected COS-7 cells and, as expected, precluded specific AVPR2 functions. As indicated by different ELISA and binding studies, the R137H mutant was almost completely retained in the cell interior. In contrast to previous studies, the few mutant receptors in the plasma membrane displayed a low (2.3-fold above basal) but significant ability to stimulate the Gs/adenylyl cyclase system. In contrast to the latter mutation, the R181C mutant is properly delivered to the cell surface but the mutation interferes with high affinity vasopressin binding. Impaired ligand binding is reflected in an about 100-fold shift of the concentration-response curve toward higher vasopressin concentrations with only slightly reduced agonist potency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • COS Cells
  • DNA
  • Diabetes Insipidus, Nephrogenic / genetics
  • Diabetes Insipidus, Nephrogenic / physiopathology*
  • Female
  • Genetic Linkage*
  • Humans
  • Male
  • Molecular Sequence Data
  • Pedigree
  • Receptors, Vasopressin / physiology*
  • X Chromosome


  • Receptors, Vasopressin
  • DNA