Equivalent gain-of-function variants in KCNK3 and KCNK9 and their contribution to distinct TASK K2P channelopathies

Crowther, Kate M., Jouen-Tachoire, Thibault R.H., Proks, Peter, Hall, Peter Rory, Veale, Emma L., Sörmann, Janina, Rödström, Karin E.J., Müller, Thomas, Wortmann, Saskia B., Barisic, Nina, and others. (2026) Equivalent gain-of-function variants in KCNK3 and KCNK9 and their contribution to distinct TASK K2P channelopathies. Journal of General Physiology, 158 (5). ISSN 0022-1295. E-ISSN 1540-7748. (doi:10.1085/jgp.202613989) (KAR id:115880)

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Official URL: https://doi.org/10.1085/jgp.202613989

Related resource
Resource title:	Equivalent gain-of-function variants in KCNK3 and KCNK9 and their contribution to distinct task K2P channelopathies
Resource type:	Other
DOI:	10.1016/j.bpj.2025.11.673
KDR/KAR URL:	https://kar.kent.ac.uk/114896/
External URL:	https://doi.org/10.1016/j.bpj.2025.11.673

Related resource
Resource title:	Equivalent Gain-of-Function Variants in KCNK3 and KCNK9 and their Contribution to Distinct TASK K2P Channelopathies
Resource type:	Pre-print
DOI:	10.64898/2025.12.15.25342159
KDR/KAR URL:	https://kar.kent.ac.uk/113226/
External URL:	https://doi.org/10.64898/2025.12.15.25342159

Abstract

Gain-of-function (GoF) missense variants in the two-pore domain (K2P) K+ channel TASK-1 (KCNK3) result in developmental delay with sleep apnea (DDSA), a neurodevelopmental channelopathy, while loss-of-function (LoF) variants cause pulmonary arterial hypertension. However, for the related TASK-3 channel (KCNK9), both LoF and GoF variants underlie a distinct neurodevelopmental disorder, KCNK9 imprinting syndrome (KIS). The relationship between genotype and phenotype in these disorders is further complicated because TASK-1 and TASK-3 can co-assemble into heteromeric channels with distinct functional properties. Here, we report additional patients with missense variants in KCNK3 and KCNK9 and investigate the effect of four novel genetic variants on the functional properties of homomeric and heteromeric TASK channels. Interestingly, two of these new pathogenic GoF variants (R131H and L122V) are found in both TASK-1 and TASK-3 and have equivalent functional effects on heteromeric TASK-1/TASK-3 channel activity, yet result in different clinical phenotypes. We have also determined a cryo-EM structure for the pathogenic L122V mutant TASK-3 channel, which suggests that subtle changes in gating and permeation within the inner cavity are responsible for its activatory effect. Overall, these results highlight the dominant role that homomeric TASK channels likely play in defining their associated channelopathies as well as the complexity of interpreting K+ channel dysfunction in pathophysiology.

Item Type:	Article
DOI/Identification number:	10.1085/jgp.202613989
Uncontrolled keywords:	biophysics; ion channels in health and disease; molecular pharmacology, pathophysiology, protein structure and dynamics
Subjects:	R Medicine
Institutional Unit:	Schools > Medway School of Pharmacy
Former Institutional Unit:	There are no former institutional units.
Funders:	Biotechnology and Biological Sciences Research Council (https://ror.org/00cwqg982)
Depositing User:	Emma Veale
Date Deposited:	10 Aug 2026 12:05 UTC
Last Modified:	11 Aug 2026 08:34 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/115880 (The current URI for this page, for reference purposes)

University of Kent Author Information

Veale, Emma L..

Creator's ORCID:	https://orcid.org/0000-0002-6778-9929
CReDIT Contributor Roles:	Writing - review and editing, Resources, Validation

Mathie, Alistair A..

Creator's ORCID:	https://orcid.org/0000-0001-6094-2890
CReDIT Contributor Roles:	Writing - review and editing, Conceptualisation, Data curation, Validation

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