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Functional Characterization of the Molecular Defects Causing Nephrogenic Diabetes Insipidus in Eight Families¹

Institut für Pharmakologie, Freie Universität Berlin (K.P., A.S., T.S.), D-14195 Berlin; Universitätsklinik und Poliklinik für Kinderheilkunde, Medizinische Fakultät (Charité) der Humboldt Universität zu Berlin (K.P., A.G., G.F.), D-10098 Berlin; Pädiatrische Nephrologie, Universitäts Kinderklinik Hamburg (K.T.), D-20246 Hamburg; and Klinik und Poliklinik für Kinder und Jugendmedizin (K.L.) and Institut für Humangenetik (M.H.), Ernst-Moritz-Arndt Universität, D-17487 Greifswald, Germany; and Department of Pediatrics, Kuopio University Hospital (J.J.), 70211 Kuopio, Finland

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

X-Linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder characterized by the excretion of abnormal large volumes of diluted urine mainly caused by mutations in the V2 vasopressin receptor (AVPR2) gene. By screening NDI patients for mutations within the AVPR2 gene we have identified three novel (I46K, F105V, I130F) and four recurrent (D85N, R106C, R113W, Q225X) mutations. In addition, a recurrent missense mutation (A147T) within the aquaporin-2 gene was identified in a female patient with autosomal recessive NDI associated with sensorineural deafness. Selected clinical data of the NDI patients were compared with the results from the in vitro studies. Functional analysis of I46K and I130F revealed reduced maximum agonist-induced cAMP responses as a result of an improper cell surface targeting. In contrast, the F105V mutation is delivered to the cell surface and displayed an unchanged maximum cAMP response, but impaired ligand binding abilities of F105V were reflected in a shifted concentration-response curve toward higher vasopressin concentrations. As the extracellularly located F105 is highly conserved among the vasopressin/oxytocin receptor family, functional analysis of this residue implicates an important role in high affinity agonist binding.

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