Aminoglycoside pretreatment partially restores the function of truncated V(2) vasopressin receptors found in patients with nephrogenic diabetes insipidus

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...

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Published in:The journal of clinical endocrinology and metabolism 2002-11, Vol.87 (11), p.5247-5257
Main Authors: Schulz, Angela, Sangkuhl, Katrin, Lennert, Thomas, Wigger, Marianne, Price, David Anthony, Nuuja, Anja, Grüters, Annette, Schultz, Günter, Schöneberg, Torsten
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Anti-Bacterial Agents - pharmacokinetics
Anti-Bacterial Agents - therapeutic use
Base Sequence
Codon
COS Cells
Cricetinae
Diabetes Insipidus, Nephrogenic - drug therapy
Diabetes Insipidus, Nephrogenic - genetics
Female
Fluorescent Antibody Technique
Gene Deletion
Gene Expression
Genetic Linkage
Gentamicins - pharmacology
Gentamicins - therapeutic use
Humans
Male
Molecular Sequence Data
Mutation
Receptors, Vasopressin - genetics
Receptors, Vasopressin - physiology
Sequence Alignment
Transfection
X Chromosome
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Summary: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.
ISSN:0021-972X
DOI:10.1210/jc.2002-020286