Abstract
Cystic fibrosis is caused by mutations in the CFTR gene, which are subdivided into six classes. Mutants of classes III and IV reach the cell surface but have limited function. Most class-III and class-IV mutants respond well to the recently approved potentiator VX-770, which opens the channel. We here revisited function and folding of some class-IV mutants and discovered that R347P is the only one that leads to major defects in folding. By this criterion and by its functional response to corrector drug VX-809, R347P qualifies also as a class-II mutation. Other class-IV mutants folded like wild-type CFTR and responded similarly to VX-809, demonstrating how function and folding are connected. Studies on both types of defects complement each other in understanding how compounds improve mutant CFTR function. This provides an attractive unbiased approach for characterizing mode of action of novel therapeutic compounds and helps address which drugs are efficacious for each cystic fibrosis disease variant.
| Original language | English |
|---|---|
| Article number | e201800172 |
| Journal | Life Science Alliance |
| Volume | 2 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Jan 2019 |
Funding
We thank Dr. Phil Thomas and Linda Millen (Department of Physiology, UT South Western Medical Center, Dallas) for generously donating the CFTR mutants, Dr. Inez Bronsveld (Department of Pulmonary Diseases University Medical Center Utrecht, Utrecht) for providing the ICM equipment, and Dr. John Riordan, University of North Carolina—Chapel Hill, Cystic Fibrosis Foundation Therapeutics, for providing antibodies. We thank Dr. Paola Vergani for critically reading the manuscript and Drs. Paola Vergani and David Sheppard for sharing unpublished results. This work was funded by the Netherlands Organization for Health Research and Development (Zon-Mw TOP grant 40-00812-98-14103 to CK van der Ent, JM Beekman, I Braakman), the Netherlands Cystic Fibrosis Foundation (HIT-CF grant), the Cystic Fibrosis Foundation (BRAAKM14XX0 to I Braakman), and Vertex Pharmaceuticals, Gilead, and Galapagos, including fees for serving on an advisory board paid to his institution from ProQR, and lecture fees paid to his institution from Teva Pharmaceuticals (CK van der Ent).