Dominant-negative effect of a missense variant in the TASK-2 (KCNK5) K+ channel associated with Balkan endemic nephropathy

• Main Authors: Reed, Alan, Bucci, Giovanna, Abd-Wahab, Firdaus, Tucker, Stephen J.
• Format: Article
• Language: English
• Published: PLOS 2016
• Subjects: QP Physiology
• Online Access: http://irep.iium.edu.my/71035/1/journal.pone.0156456.PDF; http://irep.iium.edu.my/71035/; https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156456
• Institution: Universiti Islam Antarabangsa Malaysia

TASK-2, a member of the Two-Pore Domain (K2P) subfamily of K+ channels, is encoded by the KCNK5 gene. The channel is expressed primarily in renal epithelial tissues and a poten- tially deleterious missense variant in KCNK5 has recently been shown to be prevalent amongst patients predisposed to the development of Balkan Endemic Nephropathy (BEN), a chronic tubulointerstitial renal disease of unknown etiology. In this study we show that this variant (T108P) results in a complete loss of channel function and is associated with a major reduction in TASK-2 channel subunits at the cell surface. Furthermore, these mutant subunits have a suppressive or ‘dominant-negative’ effect on channel function when coex- pressed with wild-type subunits. This missense variant is located at the extracellular surface of the M2 transmembrane helix and by using a combination of structural modelling and fur- ther functional analysis we also show that this highly-conserved threonine residue is critical for the correct function of other K2P channels. These results therefore provide further struc- tural and functional insights into the possible pathophysiological effects of this missense variant in TASK-2.