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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Janina Sörmann - , University of Oxford (Author)
  • Marcus Schewe - , Kiel University (Author)
  • Peter Proks - , University of Oxford (Author)
  • Thibault Jouen-Tachoire - , University of Oxford (Author)
  • Shanlin Rao - , University of Oxford (Author)
  • Elena B. Riel - , Kiel University (Author)
  • Katherine E. Agre - , Mayo Clinic Rochester, MN (Author)
  • Amber Begtrup - , GeneDX Inc (Author)
  • John Dean - , NHS Grampian (Author)
  • Maria Descartes - , University of Alabama at Birmingham (Author)
  • Alice Gardham - , London North West University Healthcare NHS Trust (Author)
  • Carrie Lahner - , Mayo Clinic Rochester, MN (Author)
  • Paul R. Mark - , Spectrum Health (Author)
  • Srikanth Muppidi - , Stanford University (Author)
  • Pavel N. Pichurin - , Mayo Clinic Rochester, MN (Author)
  • Joseph Porrmann - , Institute of Clinical Genetics, University Hospital Carl Gustav Carus Dresden, TUD Dresden University of Technology (Author)
  • Jens Schallner - , Department of Paediatrics, Division of Neuropediatrics, TUD Dresden University of Technology (Author)
  • Kirstin Smith - , University of Alabama at Birmingham (Author)
  • Volker Straub - , Newcastle University (Author)
  • Pradeep Vasudevan - , Leicester Royal Infirmary (Author)
  • Rebecca Willaert - , GeneDX Inc (Author)
  • Elisabeth P. Carpenter - , University of Oxford (Author)
  • Karin E.J. Rödström - , University of Oxford (Author)
  • Michael G. Hahn - , Bayer AG (Author)
  • Thomas Müller - , Bayer AG (Author)
  • Thomas Baukrowitz - , Kiel University (Author)
  • Matthew E. Hurles - , Wellcome Sanger Institute (Author)
  • Caroline F. Wright - , University of Exeter (Author)
  • Stephen J. Tucker - , University of Oxford (Author)

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.

Details

Original languageEnglish
Pages (from-to)1534-1543
Number of pages10
JournalNature genetics
Volume54
Issue number10
Publication statusPublished - Oct 2022
Peer-reviewedYes

External IDs

PubMed 36195757

Keywords

Sustainable Development Goals

ASJC Scopus subject areas