ArticleJournal of cardiovascular electrophysiology2013
An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia.
Article in Journal of cardiovascular electrophysiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 34 citations in OpenAlex.
- Genetics of sinoatrial node function and heart rate disorders.Disease models & mechanisms · 2023Review
- Regulation of HCN Channels by Protein Interactions.Frontiers in physiology · 2022Review
- Review: HCN Channels in the Heart.Current cardiology reviews · 2022Review
- Changes in peripheral HCN2 channels during persistent inflammation.Channels (Austin, Tex.) · 2021Article
- The focal adhesion protein Testin modulates KCNE2 potassium channel β subunit activity.Channels (Austin, Tex.) · 2021Article
- Cardiac and neuronal HCN channelopathies.Pflugers Archiv : European journal of physiology · 2020Review
- Calcium Handling Defects and Cardiac Arrhythmia Syndromes.Frontiers in pharmacology · 2020Review
- Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.American journal of human genetics · 2019Article
- Disease-linked mutations alter the stoichiometries of HCN-KCNE2 complexes.Scientific reports · 2019Article
- AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2-dependent sudden cardiac death.Physiological reports · 2019Article
- Long QT Syndrome and Sinus Bradycardia-A Mini Review.Frontiers in cardiovascular medicine · 2018Review
- Review
- Molecular Pathophysiology of Congenital Long QT Syndrome.Physiological reviews · 2017Review
- Mutation in S6 domain of HCN4 channel in patient with suspected Brugada syndrome modifies channel function.Pflugers Archiv : European journal of physiology · 2016Article
- Genetic analysis of Iranian family with hereditary cardiac arrhythmias by next generation sequencing.Advanced biomedical research · 2016Article
- Review
- HCN4, Sinus Bradycardia and Atrial Fibrillation.Arrhythmia & electrophysiology review · 2015Article
- Pacemaker activity of the human sinoatrial node: an update on the effects of mutations in HCN4 on the hyperpolarization-activated current.International journal of molecular sciences · 2015Review
- Dysfunctional HCN ion channels in neurological diseases.Frontiers in cellular neuroscience · 2015Article
- Pacemaker gene mutations, bradycardia, arrhythmias and the coupled clock theory.Journal of cardiovascular electrophysiology · 2013Article
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9 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundSinus node (SN) dysfunction is observed in some long-QT syndrome (LQTS) patients, but has not been studied as a function of LQTS genotype. LQTS6 involves mutations in the hERG β-subunit MiRP1, which also interacts with hyperpolarization-activated, cyclic nucleotide gated (HCN) channels-the molecular correlate of SN pacemaker current (If ). An LQTS registry search identified a 55-year male with M54T MiRP1 mutation, history of sinus bradycardia (39-56 bpm), and prolonged QTc.
objectiveWe tested if LQTS6 incorporates sinus bradycardia due to abnormal If .
methodsWe transiently co-transfected neonatal rat ventricular myocytes (to study currents in a myocyte background) with human HCN4 (hHCN4, primary SN isoform) or human HCN2 (hHCN2) and one of the following: empty vector, wild-type hMiRP1 (WT), M54T hMiRP1 (M54T). Current amplitude, voltage dependence, and kinetics were measured by whole cell patch clamp.
resultsM54T co-expression decreased HCN4 current density by 80% compared to hHCN4 alone or with WT, and also slowed HCN4 activation at physiologically relevant voltages. Neither WT nor M54T altered HCN4 voltage dependence. A computer simulation predicts that these changes in HCN4 current would decrease rate and be additive with published effects of M54T mutation on hERG kinetics on rate.
conclusionsWe conclude that M54T LQTS6 mutation can cause sinus bradycardia through effects on both hERG and HCN currents. Patients with other LQTS6 mutations should be examined for SN dysfunction, and the effect on HCN current determined.
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