A KCNK16 mutation causing TALK-1 gain of function is associated with maturity-onset diabetes of the young.

Autor: Graff SM; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA., Johnson SR; Department of Endocrinology, Queensland Children's Hospital, South Brisbane, Queensland, Australia.; Translational Genomics Group, Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.; Faculty of Medicine, University of Queensland, Herston, Queensland, Australia., Leo PJ; Translational Genomics Group, Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia., Dadi PK; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA., Dickerson MT; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA., Nakhe AY; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA., McInerney-Leo AM; Dermatology Research Centre, Dermatology Research Centre, The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia., Marshall M; Translational Genomics Group, Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia., Zaborska KE; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA., Schaub CM; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA., Brown MA; Guy's and St Thomas' NHS Foundation Trust and King's College London NIHR Biomedical Research Centre, King's College London, London, United Kingdom., Jacobson DA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA., Duncan EL; Faculty of Medicine, University of Queensland, Herston, Queensland, Australia.; Department of Twin Research & Genetic Epidemiology, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2021 Jul 08; Vol. 6 (13). Date of Electronic Publication: 2021 Jul 08.
DOI: 10.1172/jci.insight.138057
Abstrakt: Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired pancreatic β cell function. The mechanisms underlying MODY include β cell KATP channel dysfunction (e.g., KCNJ11 [MODY13] or ABCC8 [MODY12] mutations); however, no other β cell channelopathies have been associated with MODY to date. Here, we have identified a nonsynonymous coding variant in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY. KCNK16 is the most abundant and β cell-restricted K+ channel transcript, encoding the two-pore-domain K+ channel TALK-1. Whole-cell K+ currents demonstrated a large gain of function with TALK-1 Leu114Pro compared with TALK-1 WT, due to greater single-channel activity. Glucose-stimulated membrane potential depolarization and Ca2+ influx were inhibited in mouse islets expressing TALK-1 Leu114Pro with less endoplasmic reticulum Ca2+ storage. TALK-1 Leu114Pro significantly blunted glucose-stimulated insulin secretion compared with TALK-1 WT in mouse and human islets. These data suggest that KCNK16 is a previously unreported gene for MODY.
Databáze: MEDLINE