Manara - Qatar Research Repository
jpm-12-00118.pdf (3.97 MB)

Clinical, Genetic and Functional Characterization of a Novel AVPR2 Missense Mutation in a Woman with X-Linked Recessive Nephrogenic Diabetes Insipidus

Download (3.97 MB)
journal contribution
submitted on 2024-04-01, 10:03 and posted on 2024-04-01, 10:03 authored by Senthil Selvaraj, Dírcea Rodrigues, Navaneethakrishnan Krishnamoorthy, Khalid A. Fakhro, Luís R. Saraiva, Manuel C. Lemos

Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by renal unresponsiveness to the hormone vasopressin, leading to excretion of large volumes of diluted urine. Mutations in the arginine vasopressin receptor-2 (AVPR2) gene cause congenital NDI and have an X-linked recessive inheritance. The disorder affects almost exclusively male family members, but female carriers occasionally present partial phenotypes due to skewed inactivation of the X-chromosome. Here, we report a rare case of a woman affected with X-linked recessive NDI, presenting an average urinary output of 12 L/day. Clinical and biochemical studies showed incomplete responses to water deprivation and vasopressin stimulation tests. Genetic analyses revealed a novel heterozygous missense mutation (c.493G > C, p.Ala165Pro) in the AVPR2 gene. Using a combination of in-silico protein modeling with human cellular models and molecular phenotyping, we provide functional evidence for phenotypic effects. The mutation destabilizes the helical structure of the AVPR2 transmembrane domains and disrupts its plasma membrane localization and downstream intracellular signaling pathways upon activation with its agonist vasopressin. These defects lead to deficient aquaporin 2 (AQP2) membrane translocation, explaining the inability to concentrate urine in this patient.

Other Information

Published in: Journal of Personalized Medicine
See article on publisher's website:



  • English



Publication Year

  • 2022

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Sidra Medicine
  • Weill Cornell Medical College in Qatar (-2015)
  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU

Usage metrics

    College of Health and Life Sciences - HBKU



    Ref. manager