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

Reed, Alan and Bucci, Giovanna and Abd-Wahab, Firdaus and Tucker, Stephen J. (2016) Dominant-negative effect of a missense variant in the TASK-2 (KCNK5) K+ channel associated with Balkan endemic nephropathy. PLOS One, 11 (5). pp. 1-12. ISSN 1932-6203

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Abstract

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.

Item Type: Article (Journal)
Additional Information: 5236/71035
Uncontrolled Keywords: missense variant, Balkan endemic nephropathy
Subjects: Q Science > QP Physiology
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button): Kulliyyah of Engineering > Department of Biotechnology Engineering
Kulliyyah of Engineering
Depositing User: Mohd Firdaus Abd Wahab
Date Deposited: 01 Apr 2019 11:09
Last Modified: 01 Apr 2019 11:09
URI: http://irep.iium.edu.my/id/eprint/71035

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