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

Lookup NU author(s): Professor Volker StraubORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022, The Author(s).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.

Publication metadata

Author(s): Sormann J, Schewe M, Proks P, Jouen-Tachoire T, Rao S, Riel EB, Agre KE, Begtrup A, Dean J, Descartes M, Fischer J, Gardham A, Lahner C, Mark PR, Muppidi S, Pichurin PN, Porrmann J, Schallner J, Smith K, Straub V, Vasudevan P, Willaert R, Carpenter EP, Rodstrom KEJ, Hahn MG, Muller T, Baukrowitz T, Hurles ME, Wright CF, Tucker SJ

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2022

Volume: 54

Issue: 10

Pages: 1534-1543

Print publication date: 01/10/2022

Online publication date: 04/10/2022

Acceptance date: 09/08/2022

Date deposited: 28/06/2023

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Research


DOI: 10.1038/s41588-022-01185-x

PubMed id: 36195757


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Funder referenceFunder name
BA 1793/6-2
Biotechnology and Biological Sciences Research Council
Department of Health
Deutsche Forschungsgemeinschaft
Medical Research Council
SCHE 2112/1–2
Wellcome Sanger Institute
Wellcome Trust