Key result
The hERG1-H70R variant in patient-specific iPSC-CMs prolonged action potentials and decreased IKr due to impaired trafficking of hERG1a and maintained expression of hERG1b.
Why the study?
It was unknown whether KCNH2 PAS domain variants impact hERG1b expression to contribute to the long QT syndrome type 2 phenotype.
The hERG1-H70R variant induces long QT syndrome type 2 by causing a hERG1a/1b subunit imbalance due to impaired hERG1a trafficking and maintained hERG1b expression.
PAS variants may drive LQT2 via isoform imbalance; leaves open whether isoform-targeted therapies alter arrhythmia risk.
Background: Inherited long QT syndrome type 2 results from variants in the KCNH2 gene encoding the human Ether-à-go-go related gene 1 (hERG1) potassium channel. Two main isoforms, hERG1a and hERG1b, assemble to form tetrameric channel. The N-terminal PAS (Per/Arnt/Sim) domain, present only on hERG1a subunits, is a hotspot for pathogenic variants, but it is unknown whether PAS domain variants impact hERG1b expression to contribute to the long QT syndrome type 2 phenotype. We aimed to use patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to investigate the pathogenesis of the hERG1a PAS domain variant hERG1-H70R. Methods: Human iPSCs were derived from a patient with long QT syndrome type 2 carrying the PAS domain variant hERG1-H70R. CRISPR/Cas9 gene editing produced isogenic control iPSC lines. Differentiated iPSC-CMs were evaluated for their electrophysiology, hERG1a/1b mRNA expression, and hERG1a/1b protein expression. Results: Action potentials from single hERG1-H70R iPSC-CMs were prolonged relative to controls, and voltage clamp studies showed an underlying decrease in I Kr with accelerated deactivation. In hERG1-H70R iPSC-CMs, transcription of hERG1a and hERG1b mRNA was unchanged compared with controls based on nascent nuclear transcript analysis, but hERG1b mRNA was significantly increased as was the ratio of hERG1b / hERG1a in mRNA complexes, suggesting posttranscriptional changes. Expression of complex glycosylated hERG1a in hERG1-H70R iPSC-CMs was reduced due to impaired protein trafficking, whereas the expression of the complex glycosylated form of hERG1b was unchanged. Conclusions: Patient-specific hERG1-H70R iPSC-CMs reveal a newly appreciated mechanism of pathogenesis of the long QT syndrome type 2 phenotype due to both impaired trafficking of hERG1a and maintained expression of hERG1b that produces subunit imbalance and reduced I Kr with accelerated deactivation. Graphic Abstract: A graphic abstract is available for this article.
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Feng et al. (2021) studied Long QT syndrome type 2. hERG1-H70R variant vs. Isogenic control iPSC lines was evaluated on Action potential duration, IKr current, and hERG1a/1b expression. The hERG1-H70R variant in patient-specific iPSC-CMs prolonged action potentials and decreased IKr due to impaired trafficking of hERG1a and maintained expression of hERG1b.
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