Tarek Dawamne

Introduction. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common potentially lethal single gene disorder. ADPKD is often associated with renal cysts that cause increased kidney malfunction such as hematuria, flank pain, kidney stones, carcinoma, in addition to other cardiovascular abnormalities¹.  Methods. Many sources were reviewed to investigate the current understanding of ADPKD pathogenesis. In some references, embryonic kidney cell cultures were grown from intercrossing mice with a mutation in the Pkd1 gene. After cell sorting, the cells in concern were grown and maintained in suspension media. After that, they were subjected to immunolocalization of PC1 and PC2. Finally, affinity-purified antibodies were produced to study the gene effects and electrophysiological effects on the cell³. Similar methods and ideas were used in most other references (4-6) to conclude associated results. Other references (7,8) studied DNA changes from cells obtained from real cases. Results. PC1 is a binding protein for PC2, a calcium channel receptor, and was found to cause an increase in intracellular Ca2+ when increased flow around the cell was sensed³. PC2 extracellular domain was found to be responsible for Ca2+ influx into the cell when sensing flow outside the cell³. Furthermore, PC1 and PC2 were found to form a complex that functions as a channel in the plasma membrane. In that complex, PC1 N-Terminus is an “indispensable activator”.⁴  Other sources reference TRPP2, a protein associated with PC2, which was proved to form a heteromultimer complex with TRPV4⁵.  Complete cleavage of PC1 was found to be important to its function and mutations in PC1 resulted in cyst formation⁶. In addition, differences in causes of PC1 folding malfunction affected the severity of ADPKD. For example, mutations in GANAB caused PC1 localization and maturations defects and were usually associated with mild renal phenotype without any renal insufficiency⁷. Other polycystic kidney disease cases caused by Pkd1 mutations were found to be associated with TSC deletions8. Conclusion. Current studies confirmed the association of the PC1/PC2 complex malfunctions with calcium signaling and the pathogenesis of polycystic kidney disease. Other studies focused on the effects of other proteins like TRPP2, or other mutations in the DNA such as GANAB and TSC. Because of the large range of ADPKD symptoms from no end stage renal failure in elderly patients to increased kidney size in utero¹, future work should be aiming to form a uniting theory that can combine all the PKD causes and their severity.

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7. Qian F, Boletta A, Bhunia AK, et . Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations. Proceedings of the National Academy of Sciences. 2002;99(26):16981-16986. doi:10.1073/pnas.252484899.
8. Porath B, Gainullin VG, Cornec-Le Gall E, et al.. Mutations in GANAB , Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. The American Journal of Human Genetics. 2016;98(6):1193-1207. doi:10.1016/j.ajhg.2016.05.004.
9. Consugar MB, Wong WC, Lundquist PA, et al.. Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome. Kidney International. 2008;74(11):1468-1479. doi:10.1038/ki.2008.485.