Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea
Janina Sörmann, Marcus Schewe, Peter Proks, Thibault Jouen-Tachoire, Shanlin Rao, Elena B. Riel, Katherine Agre, Amber Begtrup, John Dean, Maria Descartes, Jan A. Fischer, Alice Gardham, Carrie A. Lahner, Paul R. Mark, Srikanth Muppidi, Pavel N. Pichurin, Joseph Porrmann, Jens Schallner, Kirstin Smith, Volker Straub, Pradeep Vasudevan, Rebecca Willaert, Elisabeth P. Carpenter, Karin E. J. Rödström, Michael G. Hahn, Thomas Müller, Thomas Baukrowitz, Matthew E. Hurles, Caroline F. Wright, Stephen J. Tucker
Abstract
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.