Date of Award
Mutations within polycystin-1 (PC1) and transcient receptor potential polycystin channel 2 (TRPP2) are the leading causes for development of the most common kidney disease, Autosomal Dominant Polycystic Kidney Disease (ADPKD). Although significant efforts have been made to investigate properties and characteristics of these proteins over the last three decades, their roles in ADPKD and how mutations in these proteins lead to cystogenesis is still largely unknown. In the current work, I have studied a novel TRPP2 mutation found in a patient family diagnosed with ADPKD that removes the stop codon and results in adding an additional twelve amino acids on the C-terminus of the translated protein. My focus is to explore the characteristics of this mutation by utilizing gain-of-function TRPP2 mutants to record channel activity. We found that the pathogenic mutation significantly reduced TRPP2 expression and trafficking, leading to reduced channel activity. Furthermore, this mutation also reduces the activity of the heteromeric PC1/TRPP2 complex channel. My results gain insight into the pathogenesis of ADPKD caused by a mutation on TRPP2. In the last part of this thesis, I have also studied the role of a potential PC1 binding partner C1orf95, the human ortholog of the STUM protein, in regulating the channel function of the PC1/TRPP2 complex
Chaudhry, Haroon Alam, "THE EFFECTS OF A PATHOGENIC MUTATION AND A BINDING PARTNER ON THE ACTIVITY OF POLYCYSTIN ION CHANNELS" (2020). Theses and Dissertations. 30.