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Aminoglycoside Pretreatment Partially Restores the Function of Truncated V₂ Vasopressin Receptors Found in Patients with Nephrogenic Diabetes Insipidus

Institut für Pharmakologie (A.S., K.S., G.S., T.S.), Freie Universität Berlin, Universitätsklinikum Benjamin Franklin, 14195 Berlin, Germany; Kinderklinik und Poliklinik (T.L.), Universitätsklinikum Benjamin Franklin, 12200 Berlin, Germany; Kinder- und Jugendklinik (M.W.), Medizinische Fakultät Universität Rostock, 18055 Rostock, Germany; Royal Manchester Children’s Hospital (D.A.P.), Pendlebury, Manchester M27 4HA, United Kingdom; Department of Paediatrics (A.N.), Central Hospital of Central Finland, 40620 Jyväskylä, Finland; and Klinik und Poliklinik für Kinderheilkunde (A.G.), Virchow-Klinikum, Medizinische Fakultät der Humboldt Universität zu Berlin, 13353 Berlin, Germany

Address all correspondence and requests for reprints to: Torsten Schöneberg, Institut für Pharmakologie, Freie Universität Berlin, Thielallee 69-73, 14195 Berlin, Germany. E-mail: schoberg{at}zedat.fu-berlin.de.

Abstract

By screening patients with X-linked nephrogenic diabetes insipidus (NDI) for mutations within the V₂ vasopressin receptor (AVPR2) gene, we have identified six novel and two recurrent mutations. Additionally, one patient revealed a genomic deletion of 3.2 kb encompassing most of the AVPR2 gene and the last exon/3'-region of C1 gene, which is in close proximity to the AVPR2 locus. In-depth characterization of the mutant AVPR2s by a combination of functional and immunological techniques allowed to gain further insight into molecular mechanisms leading to the receptor dysfunction. Aiming at the functional reconstitution of mutant G protein-coupled receptors, several strategies of potential therapeutic usefulness have been tested. Because the functional rescue of truncated receptors is most challenging, we addressed this issue by applying an aminoglycoside approach. Here, we demonstrate that the misreading capacity of the aminoglycoside antibiotic geneticin was sufficient to restore function of mutant AVPR2s harboring premature stop codons in an in vitro expression system.

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