S-Space College of Medicine/School of Medicine (의과대학/대학원) Molecular and Genomic Medicine (분자유전체의학전공) Journal Papers (저널논문_분자유전체의학전공)
Molecular genetic study of congenital nephrogenic diabetes insipidus and rescue of mutant vasopressin V2 receptor by chemical chaperones
- Cheong, Hae Il; Cho, Hee Yeon; Park, Hye Won; Ha, Il Soo; Choi, Yong
- Issue Date
- Nephrology (Carlton). 2007 Apr;12(2):113-7.
- Animals; Arginine Vasopressin/genetics/*metabolism; COS Cells; Cell Membrane/metabolism; Cercopithecus 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
- 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.
- 1320-5358 (Print)
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