Molecular genetic study of congenital nephrogenic diabetes insipidus and rescue of mutant vasopressin V2 receptor by chemical chaperones.

Abstract

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 degrees 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.

• Authors: Hae Il Cheong, Hee Yeon Cho, Hye Won Park, Il Soo Ha, Yong Choi
• Journal: Nephrology (Carlton, Vic.) (Nephrology (Carlton)) Vol. 12 Issue 2 Pg. 113-7 (Apr 2007) ISSN: 1320-5358 [Print] Australia
• PMID: 17371330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Methylamines
• Molecular Chaperones
• Receptors, Vasopressin
• Arginine Vasopressin
• trimethylamine
• Dimethyl Sulfoxide

Topics

• Animals
• Arginine Vasopressin (genetics, metabolism)
• COS Cells
• Cell Membrane (metabolism)
• Chlorocebus aethiops
• Diabetes Insipidus, Nephrogenic (genetics, metabolism)
• Dimethyl Sulfoxide (pharmacology)
• Humans
• Male
• Methylamines (pharmacology)
• Molecular Chaperones (pharmacology)
• Mutation
• Mutation, Missense
• Point Mutation
• Protein Folding
• Protein Transport (drug effects)
• Receptors, Vasopressin (chemistry, genetics, metabolism)
• Temperature
• Transfection