title: Aminoglycoside pretreatment partially restores the function of truncated V(2) vasopressin receptors found in patients with nephrogenic diabetes insipidus.
abstract: By screening patients with X-linked nephrogenic diabetes insipidus (NDI) for mutations within the V(2) 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.
authors.affiliation: Institut für Pharmakologie, Freie Universität Berlin, Universitätsklinikum Benjamin Franklin, Thielallee 69-73, 14195 Berlin, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
authors.forename: Katrin
authors.initials: K
authors.lastname: Sangkuhl
authors.forename: Thomas
authors.initials: T
authors.lastname: Lennert
authors.forename: Marianne
authors.initials: M
authors.lastname: Wigger
authors.forename: David Anthony
authors.initials: DA
authors.lastname: Price
authors.forename: Anja
authors.initials: A
authors.lastname: Nuuja
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters
authors.forename: Günter
authors.initials: G
authors.lastname: Schultz
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001483:Base Sequence; D019556:COS Cells; D003062:Codon; D006224:Cricetinae; D018500:Diabetes Insipidus, Nephrogenic / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D015870:Gene Expression; D008040:Genetic Linkage; D005839:Gentamicins / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D017483:Receptors, Vasopressin / Q000235:genetics* / Q000502:physiology*; D016415:Sequence Alignment; D014162:Transfection; D014960:X Chromosome
chemical_list: D000900:Anti-Bacterial Agents; D003062:Codon; D005839:Gentamicins; D017483:Receptors, Vasopressin; C010680:antibiotic G 418