Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea

Abstract

Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K+ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a new developmental disorder with associated sleep apnea (developmental delay with sleep apnea, or DDSA) caused by rare de novo gain-of-function mutations in KCNK3. The mutations cluster around the ‘X-gate’, a gating motif that controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways. However, despite their defective X-gating, these mutant channels can still be inhibited by a range of known TASK channel inhibitors. These results not only highlight an important new role for TASK-1 K+ channels and their link with sleep apnea but also identify possible therapeutic strategies.

Interpreting the molecular mechanisms of disease variants in human transmembrane proteins

“…We observe a number of pathogenic variants with very negative ΔΔG that indicates a stabilizing effect on the structure. As also recently shown by (69), gain of function variants can lead to pathogenicity, those variants we observe might be explained in a similar way. To confirm, more information and benchmark is needed.…”

Development of covalent chemogenetic K2Pchannel activators

“…Leak potassium currents produced by K 2P channels play a fundamental role in membrane potential stabilization and cellular excitability regulation 1,2 . Consequently, K 2P s are important to normal and pathophysiological processes 2,3 such as action potential propagation 4,5 , pain 6-8 , sleep 9 , intraocular pressure 10 , retinal visual processing 11 , migraine 12 , depression 13 , pulmonary hypertension 14 , and sleep apnea 15 . Because of their strong effects on cellular excitability, K 2P s are highly regulated by a variety of physiological cues and regulatory pathways 2 .…”

Physiological and pathophysiological roles of the KCNK3 potassium channel in the pulmonary circulation and the heart

“…3). In addition, six gain‐of‐function variants were identified in sleep apnoea patients (Sörmann et al., 2022), which could have consequences for heart function since heart dysfunctions are risk factors for sleep apnoea development, and the poor quality of life of these patients could lead to cardiovascular diseases (Jordan et al., 2014).…”