Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea. Academic Article uri icon

Overview

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.

authors

  • Sörmann, Janina
  • Schewe, Marcus
  • Proks, Peter
  • Jouen-Tachoire, Thibault
  • Rao, Shanlin
  • Riel, Elena
  • 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

publication date

  • October 4, 2022

Research

keywords

  • Gain of Function Mutation
  • Sleep Apnea Syndromes

Identity

PubMed Central ID

  • PMC9534757

Scopus Document Identifier

  • 85139226380

Digital Object Identifier (DOI)

  • 10.1016/j.jmb.2019.06.003

PubMed ID

  • 36195757

Additional Document Info

volume

  • 54

issue

  • 10