Molecular Bases of Disease
- Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of cysts, leading to a decline in function and renal failure that cannot be prevented by current treatments. Mutations in pkd1 and pkd2, encoding the polycystin 1 and 2 proteins, induce growth-related pathways, including heat shock proteins, as occurs in some cancers, raising the prospect that pharmacological interventions that target these pathways might alleviate or prevent ADPKD. Here, we demonstrate a role for VX-809, a corrector of cystic fibrosis transmembrane conductance regulator (CFTR), conventionally used to manage cystic fibrosis in reducing renal cyst growth.
- Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of multiple renal cysts, often leading to renal failure that cannot be prevented by a current treatment. Two proteins encoded by two genes are associated with ADPKD: PC1 (pkd1), primarily a signaling molecule, and PC2 (pkd2), a Ca2+ channel. Dysregulation of cAMP signaling is central to ADPKD, but the molecular mechanism is unresolved. Here, we studied the role of histone deacetylase 6 (HDAC6) in regulating cyst growth to test the possibility that inhibiting HDAC6 might help manage ADPKD.
- Background: Mutations in nucleotide binding domain 1 of cystic fibrosis (CF) transmembrane conductance regulator cause severe CF.Results: Correctors rescue trafficking of ΔF508 by altering interaction with Hsp27 and −40.Conclusion: Rescue of trafficking mutants can be accomplished by combining correctors from different classes.Significance: ΔF508 is the most common mutation. Information on the mechanism of corrector action is critical for treating the majority of patients.
- Background: Mutations in nucleotide binding domain 1 of ABCA4 cause Stargardt Disease.Results: Correctors rescue trafficking of NBD1 mutants by altering a proteostatic network of quality control proteins.Conclusion: Rescue of trafficking ABCA 4 mutants can be accomplished by correctors similar to CFTR.Significance: There is currently no treatment for Stargardt macular degeneration.