Premium
Molecular genetic study of congenital nephrogenic diabetes insipidus and rescue of mutant vasopressin V2 receptor by chemical chaperones
Author(s) -
CHEONG HAE IL,
CHO HEE YEON,
PARK HYE WON,
HA IL SOO,
CHOI YONG
Publication year - 2007
Publication title -
nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 61
eISSN - 1440-1797
pISSN - 1320-5358
DOI - 10.1111/j.1440-1797.2006.00759.x
Subject(s) - nephrogenic diabetes insipidus , arginine vasopressin receptor 2 , missense mutation , chemical chaperone , mutant , diabetes insipidus , receptor , vasopressin , medicine , endocrinology , mutation , point mutation , arginine , microbiology and biotechnology , gene , biology , genetics , amino acid , antagonist
SUMMARY: Aim: X‐linked nephrogenic diabetes insipidus is a rare disease caused by mutations in the arginine vasopressin V2 receptor ( AVPR2 ) gene, which encodes vasopressin V2 receptor (V2R) . More than a half of reported mutations in AVPR2 are missense mutations, and a large number of missense mutant receptors fail to fold properly and therefore are not routed to the cell surface. Methods: We analysed the AVPR2 gene in 14 unrelated patients with X‐linked nephrogenic diabetes insipidus, and found 13 different mutations including eight missense point mutations. The cellular expression patterns of three missense mutant (A98P, L274P and R113W) and wild‐type V2R were determined in transfected COS‐7 cells. Results: In contrast to wild‐type V2R, the cell‐surface expressions of mutant receptors were totally (A98P and L274P) or partially (R113W) absent. Instead, they were retained intracellularly. However, treatment of cells with two chemical chaperones (100 mmol/L trimethylamine oxide or 2% dimethyl sulfoxide) or incubation at 26°C restored the cell‐surface expressions of mutant receptors. Conclusion: These data show that some chemical chaperones correct the mistrafficking of misfolded A98P, L274P and R113W V2R. Thus, we believe that a therapeutic strategy based on chemical chaperones in patients with these mutations is worth trying.