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A Possible Explanation for the Low Penetrance of Pathogenic KCNE1 Variants in Long QT Syndrome Type 5.

Szilvia DériTeodóra HartaiLászló VirágNorbert JostAlain J LabroAndrás VarróIstvan BaczkoStanley NattelBalázs Ördög
Published in: Pharmaceuticals (Basel, Switzerland) (2022)
Long QT syndrome (LQTS) is an inherited cardiac rhythm disorder associated with increased incidence of cardiac arrhythmias and sudden death. LQTS type 5 (LQT5) is caused by dominant mutant variants of KCNE1, a regulatory subunit of the voltage-gated ion channels generating the cardiac potassium current I Ks . While mutant LQT5 KCNE1 variants are known to inhibit I Ks amplitudes in heterologous expression systems, cardiomyocytes from a transgenic rabbit LQT5 model displayed unchanged I Ks amplitudes, pointing towards the critical role of additional factors in the development of the LQT5 phenotype in vivo. In this study, we demonstrate that KCNE3, a candidate regulatory subunit of I Ks channels minimizes the inhibitory effects of LQT5 KCNE1 variants on I Ks amplitudes, while current deactivation is accelerated. Such changes recapitulate I Ks properties observed in LQT5 transgenic rabbits. We show that KCNE3 accomplishes this by displacing the KCNE1 subunit within the I Ks ion channel complex, as evidenced by a dedicated biophysical assay. These findings depict KCNE3 as an integral part of the I Ks channel complex that regulates I Ks function in cardiomyocytes and modifies the development of the LQT5 phenotype.
Keyphrases
  • copy number
  • left ventricular
  • poor prognosis
  • transcription factor
  • risk factors
  • case report
  • atrial fibrillation
  • dna methylation
  • protein kinase
  • binding protein
  • saccharomyces cerevisiae