Kate M. Crowther, Thibault R. H. Jouen-Tachoire, Peter Proks, Peter Rory Hall, Emma L. Veale, Janina Sörmann, Karin E. J. Rödström, Thomas Müller, Saskia B. Wortmann, Nina Barisic, Natalie Hauser, Vincenzo Salpietro, RaeLynn Forsyth, Linford Williams, Nora Derrabi, Carlos A. Bacino, Jill A. Rosenfeld, Henry Houlden, Simon Newstead, Caroline F. Wright, James Fasham, Alistair A. Mathie, Reza Maroofian, Stephen J. Tucker
University of Oxford. Scripps Research Institute. Universities of Greenwich and Kent at Medway. University of Westminster. Bayer AG. University Children’s Hospital and Paracelsus Medical University. University Hospital Centre Split and University of Zagreb School of Medicine. Inova Fairfax Hospital. UCL Queen Square Institute of Neurology. UPMC Children’s Hospital of Pittsburgh. CHU Ibn Rochd Hospital. Baylor College of Medicine and Baylor Genetics Laboratories. University of Exeter Medical School. Royal Devon & Exeter Hospital.
United Kingdom, United States, Germany, Austria, Croatia and Morocco
Journal of General Physiology
J Gen Physiol 2026; 158:
DOI: 10.1085/jgp.202613989
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.
Category
Class I. Heritable Pulmonary Hypertension
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes