TY - JOUR
T1 - The Linkage Phase of the Polymorphism KCNH2-K897T Influences the Electrophysiological Phenotype in hiPSC Models of LQT2
AU - van den Brink, Lettine
AU - Brandão, Karina O.
AU - Yiangou, Loukia
AU - Blanch-Asensio, Albert
AU - Mol, Mervyn P.H.
AU - Mummery, Christine L.
AU - Verkerk, Arie O.
AU - Davis, Richard P.
N1 - Funding Information: This study was supported by STEMCARDIORISK, a Starting Grant from the European Research Council (ERC) under the European Union?s Horizon 2020 Research and Innovation program (H2020 European Research Council; grant agreement #638030), a VIDI fellowship from the Netherlands Organization for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO); ILLUMINATE; #91715303), and the Netherlands Organ-on-Chip Initiative, an NWO Gravitation project (#024.003.001) funded by the Ministry of Education, Culture and Science of the government of the Netherlands. Funding Information: This study was supported by STEMCARDIORISK, a Starting Grant from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation program (H2020 European Research Council; grant agreement #638030), a VIDI fellowship from the Netherlands Organization for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO); ILLUMINATE; #91715303), and the Netherlands Organ-on-Chip Initiative, Publisher Copyright: Copyright © 2021 van den Brink, Brandão, Yiangou, Blanch-Asensio, Mol, Mummery, Verkerk and Davis.
PY - 2021/12/16
Y1 - 2021/12/16
N2 - While rare mutations in ion channel genes are primarily responsible for inherited cardiac arrhythmias, common genetic variants are also an important contributor to the clinical heterogeneity observed among mutation carriers. The common single nucleotide polymorphism (SNP) KCNH2-K897T is associated with QT interval duration, but its influence on the disease phenotype in patients with long QT syndrome type 2 (LQT2) remains unclear. Human induced pluripotent stem cells (hiPSCs), coupled with advances in gene editing technologies, are proving an invaluable tool for modeling cardiac genetic diseases and identifying variants responsible for variability in disease expressivity. In this study, we have used isogenic hiPSC-derived cardiomyocytes (hiPSC-CMs) to establish the functional consequences of having the KCNH2-K897T SNP in cis- or trans-orientation with LQT2-causing missense variants either within the pore-loop domain (KCNH2A561T/WT) or tail region (KCNH2N996I/WT) of the potassium ion channel, human ether-a-go-go-related gene (hERG). When KCNH2-K897T was on the same allele (cis) as the primary mutation, the hERG channel in hiPSC-CMs exhibited faster activation and deactivation kinetics compared to their trans-oriented counterparts. Consistent with this, hiPSC-CMs with KCNH2-K897T in cis orientation had longer action and field potential durations. Furthermore, there was an increased occurrence of arrhythmic events upon pharmacological blocking of hERG. Collectively, these results indicate that the common polymorphism KCNH2-K897T differs in its influence on LQT2-causing KCNH2 mutations depending on whether it is present in cis or trans. This study corroborates hiPSC-CMs as a powerful platform to investigate the modifying effects of common genetic variants on inherited cardiac arrhythmias and aids in unraveling their contribution to the variable expressivity of these diseases.
AB - While rare mutations in ion channel genes are primarily responsible for inherited cardiac arrhythmias, common genetic variants are also an important contributor to the clinical heterogeneity observed among mutation carriers. The common single nucleotide polymorphism (SNP) KCNH2-K897T is associated with QT interval duration, but its influence on the disease phenotype in patients with long QT syndrome type 2 (LQT2) remains unclear. Human induced pluripotent stem cells (hiPSCs), coupled with advances in gene editing technologies, are proving an invaluable tool for modeling cardiac genetic diseases and identifying variants responsible for variability in disease expressivity. In this study, we have used isogenic hiPSC-derived cardiomyocytes (hiPSC-CMs) to establish the functional consequences of having the KCNH2-K897T SNP in cis- or trans-orientation with LQT2-causing missense variants either within the pore-loop domain (KCNH2A561T/WT) or tail region (KCNH2N996I/WT) of the potassium ion channel, human ether-a-go-go-related gene (hERG). When KCNH2-K897T was on the same allele (cis) as the primary mutation, the hERG channel in hiPSC-CMs exhibited faster activation and deactivation kinetics compared to their trans-oriented counterparts. Consistent with this, hiPSC-CMs with KCNH2-K897T in cis orientation had longer action and field potential durations. Furthermore, there was an increased occurrence of arrhythmic events upon pharmacological blocking of hERG. Collectively, these results indicate that the common polymorphism KCNH2-K897T differs in its influence on LQT2-causing KCNH2 mutations depending on whether it is present in cis or trans. This study corroborates hiPSC-CMs as a powerful platform to investigate the modifying effects of common genetic variants on inherited cardiac arrhythmias and aids in unraveling their contribution to the variable expressivity of these diseases.
KW - arrhythmia
KW - cardiac electrophysiology
KW - disease modeling
KW - genetic modifier
KW - hERG
KW - human pluripotent stem cell-derived cardiomyocytes
KW - isogenic
KW - long QT syndrome type 2
UR - http://www.scopus.com/inward/record.url?scp=85122254125&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fphys.2021.755642
DO - https://doi.org/10.3389/fphys.2021.755642
M3 - Article
C2 - 34992545
SN - 1664-042X
VL - 12
JO - Frontiers in physiology
JF - Frontiers in physiology
M1 - 755642
ER -