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      Functional characterization of AVPR2 mutants found in Turkish patients with nephrogenic diabetes insipidus

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          Diabetes insipidus is a rare disorder characterized by an impairment in water balance because of the inability to concentrate urine. While central diabetes insipidus is caused by mutations in the AVP, the reason for genetically determined nephrogenic diabetes insipidus can be mutations in AQP2 or AVPR2. After release of AVP from posterior pituitary into blood stream, it binds to AVPR2, which is one of the receptors for AVP and is mainly expressed in principal cells of collecting ducts of kidney. Receptor activation increases cAMP levels in principal cells, resulting in the incorporation of AQP2 into the membrane, finally increasing water reabsorption. This pathway can be altered by mutations in AVPR2 causing nephrogenic diabetes insipidus. In this study, we functionally characterize four mutations (R68W, ΔR67-G69/G107W, V162A and T273M) in AVPR2, which were found in Turkish patients. Upon AVP stimulation, R68W, ΔR67-G69/G107W and T273M showed a significantly reduced maximum in cAMP response compared to wild-type receptor. All mutant receptor proteins were expressed at the protein level; however, R68W, ΔR67-G69/G107W and T273M were partially retained in the cellular interior. Immunofluorescence studies showed that these mutant receptors were trapped in ER and Golgi apparatus. The function of V162A was indistinguishable from the indicating other defects causing disease. The results are important for understanding the influence of mutations on receptor function and cellular trafficking. Therefore, characterization of these mutations provides useful information for further studies addressing treatment of intracellularly trapped receptors with cell-permeable antagonists to restore receptor function in patients with nephrogenic diabetes insipidus.

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          Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants.

          Over 150 mutations within the coding sequence of the V2 vasopressin receptor (V2R) gene are known to cause nephrogenic diabetes insipidus (NDI). A large number of these mutant receptors fail to fold properly and therefore are not routed to the cell surface. Here we show that selective, nonpeptidic V2R antagonists dramatically increase cell-surface expression and rescue the function of 8 mutant NDI-V2Rs by promoting their proper folding and maturation. A cell-impermeant V2R antagonist could not mimic these effects and was unable to block the rescue mediated by a permeant agent, indicating that the nonpeptidic antagonists act intracellularly, presumably by binding to and stabilizing partially folded mutants. In addition to opening new therapeutic avenues for NDI patients, these data demonstrate that by binding to newly synthesized mutant receptors, small ligands can act as pharmacological chaperones, promoting the proper folding and maturation of receptors and their targeting to the cell surface.
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            Mutant G-protein-coupled receptors as a cause of human diseases.

            G-protein-coupled receptors (GPCR) are involved in directly and indirectly controlling an extraordinary variety of physiological functions. Their key roles in cellular communication have made them the target for more than 60% of all currently prescribed drugs. Mutations in GPCR can cause acquired and inherited diseases such as retinitis pigmentosa (RP), hypo- and hyperthyroidism, nephrogenic diabetes insipidus, several fertility disorders, and even carcinomas. To date, over 600 inactivating and almost 100 activating mutations in GPCR have been identified which are responsible for more than 30 different human diseases. The number of human disorders is expected to increase given the fact that over 160 GPCR have been targeted in mice. Herein, we summarize the current knowledge relevant to understanding the molecular basis of GPCR function, with primary emphasis on the mechanisms underlying GPCR malfunction responsible for different human diseases.
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              Molecular biology of hereditary diabetes insipidus.

              The identification, characterization, and mutational analysis of three different genes-the arginine vasopressin gene (AVP), the arginine vasopressin receptor 2 gene (AVPR2), and the vasopressin-sensitive water channel gene (aquaporin 2 [AQP2])-provide the basis for understanding of three different hereditary forms of "pure" diabetes insipidus: Neurohypophyseal diabetes insipidus, X-linked nephrogenic diabetes insipidus (NDI), and non-X-linked NDI, respectively. It is clinically useful to distinguish two types of hereditary NDI: A "pure" type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients who have congenital NDI and bear mutations in the AVPR2 or AQP2 genes have a "pure" NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride, and calcium. Patients who bear inactivating mutations in genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA and CLCNKB in combination, or BSND) that encode the membrane proteins of the thick ascending limb of the loop of Henle have a complex polyuro-polydipsic syndrome with loss of water, sodium, chloride, calcium, magnesium, and potassium. These advances provide diagnostic and clinical tools for physicians who care for these patients.

                Author and article information

                Endocr Connect
                Endocr Connect
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                January 2018
                08 November 2017
                : 7
                : 1
                : 56-64
                [1 ]Department of Biology Faculty of Science, Hacettepe University, Ankara, Turkey
                [2 ]Rudolf Schönheimer Institute of Biochemistry Faculty of Medicine, Leipzig University, Leipzig, Germany
                [3 ]Department of Endocrinology SBÜ Sultan Abdülhamid Han Teaching Hospital, Istanbul, Turkey
                Author notes
                Correspondence should be addressed to B Erdem: beril@ 123456hacettepe.edu.tr
                © 2018 The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.


                avpr2, diabetes insipidus, gpcr, functional analysis


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