title: Dominant-Negative Effect of a Missense Variant in the TASK-2 (KCNK5) K+ Channel Associated with Balkan Endemic Nephropathy.
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 potentially 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 coexpressed 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 further 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 structural and functional insights into the possible pathophysiological effects of this missense variant in TASK-2.
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, United Kingdom.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Reed
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, United Kingdom.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bucci
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, United Kingdom.
authors.forename: Firdaus
authors.initials: F
authors.lastname: Abd-Wahab
authors.affiliation: Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, United Kingdom.|OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tucker
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001449:Balkan Nephropathy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020125:Mutation, Missense; D009865:Oocytes / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: C410295:KCNK5 protein, human; D024683:Potassium Channels, Tandem Pore Domain