A polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts

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Grosch, Melanie ; Brunner, Katrin ; Ilyaskin, Alexandr V. ; Schober, Michael ; Staudner, Tobias ; Schmied, Denise ; Stumpp, Tina ; Schmidt, Kerstin N. ; Madej, M. Gregor ; Pessoa, Thaissa D. ; Othmen, Helga ; Kubitza, Marion ; Osten, Larissa ; de Vries, Uwe ; Mair, Magdalena ; Somlo, Stefan ; Moser, Markus ; Kunzelmann, Karl ; Ziegler, Christine ; Haerteis, Silke ; Korbmacher, Christoph ; Witzgall, Ralph:
A polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts.
In: Journal of Cell Science. Bd. 134 (2021) Heft 16 . - jcs259013.
ISSN 1477-9137
DOI: https://doi.org/10.1242/jcs.259013

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Abstract

Mutations in the PKD2 gene cause autosomal-dominant polycystic kidney disease but the physiological role of polycystin-2, the protein product of PKD2, remains elusive. Polycystin-2 belongs to the transient receptor potential (TRP) family of non-selective cation channels. To test the hypothesis that altered ion channel properties of polycystin-2 compromise its putative role in a control circuit controlling lumen formation of renal tubular structures, we generated a mouse model in which we exchanged the pore loop of polycystin-2 with that of the closely related cation channel polycystin-2L1 (encoded by PKD2L1), thereby creating the protein polycystin-2poreL1. Functional characterization of this mutant channel in Xenopus laevis oocytes demonstrated that its electrophysiological properties differed from those of polycystin-2 and instead resembled the properties of polycystin-2L1, in particular regarding its permeability for Ca2+ ions. Homology modeling of the ion translocation pathway of polycystin-2poreL1 argues for a wider pore in polycystin-2poreL1 than in polycystin-2. In Pkd2poreL1 knock-in mice in which the endogenous polycystin-2 protein was replaced by polycystin-2poreL1 the diameter of collecting ducts was increased and collecting duct cysts developed in a strain-dependent fashion.