title: Novel mutation in the AVPR2 gene in a Danish male with nephrogenic diabetes insipidus caused by ER retention and subsequent lysosomal degradation of the mutant receptor.
abstract: Mutations in the arginine vasopressin receptor 2 (AVPR2) gene can cause X-linked nephrogenic diabetes insipidus (NDI) characterized by the production of large amounts of urine and an inability to concentrate urine in response to the antidiuretic hormone vasopressin. We have identified a novel mutation in the AVPR2 gene (L170P) located in the fourth transmembrane domain in a Danish NDI male. Analysis of the mutant receptor in Madin-Darby Canine Kidney cell culture revealed that AVPR2-L170P was retained in the endoplasmic reticulum, and the expression was dramatically downregulated compared to wild-type AVPR2. Inhibition of the lysosome resulted in increased intracellular accumulation of AVPR2-L170P, indicating that AVPR2-L170P is downregulated via the lysosome. Inhibition of the proteasome resulted in plasma membrane localization of AVPR2-L170P, although the overall levels of AVPR2-L170P were unchanged.
authors.affiliation: Department of Biology, Stanford University, Stanford, CA, USA.
authors.forename: Lene N
authors.initials: LN
authors.lastname: Nejsum
authors.forename: Tomas M
authors.initials: TM
authors.lastname: Christensen
authors.forename: Joris H
authors.initials: JH
authors.lastname: Robben
authors.forename: Graeme
authors.initials: G
authors.lastname: Milligan
authors.forename: Peter M T
authors.initials: PM
authors.lastname: Deen
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bichet
authors.forename: Klaus
authors.initials: K
authors.lastname: Levin