Ion channels are selective pores in cell membranes. Flow of ions creates a potential difference across the cell membrane (membrane potential). The membrane potential of a cell regulates many biological processes, e.g., nerve conduction and muscle contraction. In turn, dysregulation of ion channels disrupts these biological processes, resulting in disease. The two-pore domain (K2P) family of K + channels are key players in the setting and maintenance of the resting membrane potential. Gain-of-function (GoF) missense variants in the TASK-1 ( KCNK3 ) K2P channel are associated with developmental delay with sleep apnea (DDSA) whilst loss-of-function (LoF) variants cause a hypertensive disorder. However, for the related TASK-3 channel ( KCNK9 ), both LoF and GoF variants appear to underlie a distinct neurodevelopmental disorder, KCNK9 imprinting syndrome (KIS). The relationship between genotype and phenotype is further complicated by the ability of TASK-1 and TASK-3 to co-assemble into heteromeric channels with distinct functional properties. We report a range of new probands with missense variants in KCNK3 and KCNK9 and investigate the effect of four novel variants on the functional properties of both homomeric and heteromeric TASK channels. Interestingly, two of these new GoF variants are found in both TASK-1 and TASK-3 and have equivalent effects on the functional activity of heteromeric TASK-1/TASK-3 channels, yet result in different clinical phenotypes. We have also determined a cryo-EM structure of the pathogenic L122V mutant TASK-3 channel which suggests its dramatic functional effect is likely due to subtle changes in gating and permeation within the inner cavity. Overall, these results highlight the dominant role that homomeric TASK channels play in defining their associated channelopathies as well as the complexity of interpreting K + channel dysfunction in pathophysiology.
Crowther et al. (Sun,) studied this question.