title: Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families.
abstract: 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.
authors.affiliation: Institut für Pharmakologie, Freie Universität Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Pasel
authors.forename: A
authors.initials: A
authors.lastname: Schulz
authors.forename: K
authors.initials: K
authors.lastname: Timmermann
authors.forename: K
authors.initials: K
authors.lastname: Linnemann
authors.forename: M
authors.initials: M
authors.lastname: Hoeltzenbein
authors.forename: J
authors.initials: J
authors.lastname: Jääskeläinen
authors.forename: A
authors.initials: A
authors.lastname: Grüters
authors.forename: G
authors.initials: G
authors.lastname: Filler
authors.forename: T
authors.initials: T
authors.lastname: Schöneberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins / Q000235:genetics*; D001127:Arginine Vasopressin / Q000378:metabolism; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D015252:Deoxyribonucleases, Type II Site-Specific / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017483:Receptors, Vasopressin / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D014162:Transfection; D014960:X Chromosome
chemical_list: C496023:AQP2 protein, human; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D015252:Deoxyribonucleases, Type II Site-Specific; C092157:endodeoxyribonuclease AflIII