Equivalent Gain-of-Function Variants in KCNK3 and KCNK9 and their Contribution to Distinct TASK K2P Channelopathies

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, whilst loss-of-function (LoF) variants cause a hypertensive disorder. 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 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 (R131H and L122V) are found in both TASK-1 and TASK-3 and have equivalent functional effects on heteromeric TASK-1/TASK-3 channels, yet result in different clinical phenotypes. We have also determined a cryoEM structure for 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.