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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PLOS
2016
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| Online Access: | http://irep.iium.edu.my/71035/ http://irep.iium.edu.my/71035/1/journal.pone.0156456.PDF |
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| 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 |
| building | IIUM Repository |
| collection | Online Access |
| 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. |
| first_indexed | 2025-11-14T17:24:08Z |
| format | Article |
| id | iium-71035 |
| institution | International Islamic University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T17:24:08Z |
| publishDate | 2016 |
| publisher | PLOS |
| recordtype | eprints |
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| 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 |
| 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 |
| title | 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_short | 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 |
| topic | QP Physiology |
| 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 |