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

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

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 d...

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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/
http://irep.iium.edu.my/71035/
http://irep.iium.edu.my/71035/
http://irep.iium.edu.my/71035/1/journal.pone.0156456.PDF
id iium-71035
recordtype eprints
spelling iium-710352019-04-01T03:09:36Z http://irep.iium.edu.my/71035/ Dominant-negative effect of a missense variant in the TASK-2 (KCNK5) K+ channel associated with Balkan endemic nephropathy Reed, Alan Bucci, Giovanna Abd-Wahab, Firdaus Tucker, Stephen J. QP Physiology 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. PLOS 2016-05-01 Article PeerReviewed application/pdf en http://irep.iium.edu.my/71035/1/journal.pone.0156456.PDF 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 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156456 10.1371/journal.pone.0160114
repository_type Digital Repository
institution_category Local University
institution International Islamic University Malaysia
building IIUM Repository
collection Online Access
language English
topic QP Physiology
spellingShingle QP Physiology
Reed, Alan
Bucci, Giovanna
Abd-Wahab, Firdaus
Tucker, Stephen J.
Dominant-negative effect of a missense variant in the TASK-2 (KCNK5) K+ channel associated with Balkan endemic nephropathy
description 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.
format Article
author Reed, Alan
Bucci, Giovanna
Abd-Wahab, Firdaus
Tucker, Stephen J.
author_facet Reed, Alan
Bucci, Giovanna
Abd-Wahab, Firdaus
Tucker, Stephen J.
author_sort Reed, Alan
title Dominant-negative effect of a missense variant in the TASK-2 (KCNK5) K+ channel associated with Balkan endemic nephropathy
title_short Dominant-negative effect of a missense variant in the TASK-2 (KCNK5) K+ channel associated with Balkan endemic nephropathy
title_full Dominant-negative effect of a missense variant in the TASK-2 (KCNK5) K+ channel associated with Balkan endemic nephropathy
title_fullStr Dominant-negative effect of a missense variant in the TASK-2 (KCNK5) K+ channel associated with Balkan endemic nephropathy
title_full_unstemmed Dominant-negative effect of a missense variant in the TASK-2 (KCNK5) K+ channel associated with Balkan endemic nephropathy
title_sort dominant-negative effect of a missense variant in the task-2 (kcnk5) k+ channel associated with balkan endemic nephropathy
publisher PLOS
publishDate 2016
url http://irep.iium.edu.my/71035/
http://irep.iium.edu.my/71035/
http://irep.iium.edu.my/71035/
http://irep.iium.edu.my/71035/1/journal.pone.0156456.PDF
first_indexed 2023-09-18T21:40:49Z
last_indexed 2023-09-18T21:40:49Z
_version_ 1777413127758938112

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