Mutation-Specific Differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes

Peter M. Kekenes-Huskey, Don E. Burgess, Bin Sun, Daniel C. Bartos, Ezekiel R. Rozmus, Corey L. Anderson, Craig T. January, Lee L. Eckhardt, Brian P. Delisle

Research output: Contribution to journalReview articlepeer-review

7 Scopus citations


The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen Syndrome) and dominant (Romano–Ward Syndrome) forms of long QT syndrome (LQTS) were identified. An abnormally long heart rate-corrected QT-interval was established as a biomarker for the risk of sudden cardiac death. Since then, the International LQTS Registry was established; a phenotypic scoring system to identify LQTS patients was devel-oped; the major genes that associate with typical forms of LQTS were identified; and guidelines for the successful management of patients advanced. In this review, we discuss the molecular and cellular mechanisms for LQTS associated with missense variants in KCNQ1 (LQT1) and KCNH2 (LQT2). We move beyond the “benign” to a “pathogenic” binary classification scheme for different KCNQ1 and KCNH2 missense variants and discuss gene-and mutation-specific differences in K+ channel dysfunction, which can predispose people to distinct clinical phenotypes (e.g., concealed, pleiotropic, severe, etc.). We conclude by discussing the emerging computational structural modeling strategies that will distinguish between dysfunctional subtypes of KCNQ1 and KCNH2 variants, with the goal of realizing a layered precision medicine approach focused on individuals.

Original languageEnglish
Article number7389
JournalInternational Journal of Molecular Sciences
Issue number13
StatePublished - Jul 1 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.


  • K channel
  • KCNH2
  • KCNQ1
  • arrhythmia
  • electrocardiogram
  • heart
  • long QT syndrome
  • molecular dynamics

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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