학술논문
Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea
Document Type
Original Paper
Author
Sörmann, Janina; Schewe, Marcus; Proks, Peter; Jouen-Tachoire, Thibault; Rao, Shanlin; Riel, Elena B.; Agre, Katherine E.; Begtrup, Amber; Dean, John; Descartes, Maria; Fischer, Jan; Gardham, Alice; Lahner, Carrie; Mark, Paul R.; Muppidi, Srikanth; Pichurin, Pavel N.; Porrmann, Joseph; Schallner, Jens; Smith, Kirstin; Straub, Volker; Vasudevan, Pradeep; Willaert, Rebecca; Carpenter, Elisabeth P.; Rödström, Karin E. J.; Hahn, Michael G.; Müller, Thomas; Baukrowitz, Thomas; Hurles, Matthew E.; Wright, Caroline F.; Tucker, Stephen J.
Source
Nature Genetics. 54(10):1534-1543
Subject
Language
English
ISSN
1061-4036
1546-1718
1546-1718
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.
Heterozygous de novo gain-of-function mutations in KCNK3, which encodes the two-pore-domain K+ channel TASK-1, cause a channelopathy characterized by developmental delay with sleep apnea.
Heterozygous de novo gain-of-function mutations in KCNK3, which encodes the two-pore-domain K