An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia

Pooja A. Nawathe, Yelena Kryukova, Ronit V. Oren, Raffaella Milanesi, Colleen E Clancy, Jonathan T. Lu, Arthur J. Moss, Dario Difrancesco, Richard B. Robinson

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

An LQTS6 M54T Mutation and Sinus Node Dysfunction Background Sinus 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. Objective We tested if LQTS6 incorporates sinus bradycardia due to abnormal If. Methods We 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. Results M54T 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. Conclusions We 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.

Original languageEnglish (US)
Pages (from-to)1021-1027
Number of pages7
JournalJournal of Cardiovascular Electrophysiology
Volume24
Issue number9
DOIs
StatePublished - Sep 2013

Fingerprint

Bradycardia
Sick Sinus Syndrome
Long QT Syndrome
Mutation
Sinoatrial Node
Muscle Cells
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Computer Simulation
Registries
Protein Isoforms
Genotype

Keywords

  • HCN2
  • HCN4
  • KCNE2
  • long-QT syndrome 6
  • M54T mutation
  • MiRP1
  • pacemaker current
  • sinus bradycardia
  • sinus node dysfunction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia. / Nawathe, Pooja A.; Kryukova, Yelena; Oren, Ronit V.; Milanesi, Raffaella; Clancy, Colleen E; Lu, Jonathan T.; Moss, Arthur J.; Difrancesco, Dario; Robinson, Richard B.

In: Journal of Cardiovascular Electrophysiology, Vol. 24, No. 9, 09.2013, p. 1021-1027.

Research output: Contribution to journalArticle

Nawathe, PA, Kryukova, Y, Oren, RV, Milanesi, R, Clancy, CE, Lu, JT, Moss, AJ, Difrancesco, D & Robinson, RB 2013, 'An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia', Journal of Cardiovascular Electrophysiology, vol. 24, no. 9, pp. 1021-1027. https://doi.org/10.1111/jce.12163
Nawathe, Pooja A. ; Kryukova, Yelena ; Oren, Ronit V. ; Milanesi, Raffaella ; Clancy, Colleen E ; Lu, Jonathan T. ; Moss, Arthur J. ; Difrancesco, Dario ; Robinson, Richard B. / An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia. In: Journal of Cardiovascular Electrophysiology. 2013 ; Vol. 24, No. 9. pp. 1021-1027.
@article{c303b2805588471cb524ef5221f07431,
title = "An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia",
abstract = "An LQTS6 M54T Mutation and Sinus Node Dysfunction Background Sinus 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. Objective We tested if LQTS6 incorporates sinus bradycardia due to abnormal If. Methods We 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. Results M54T 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. Conclusions We 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.",
keywords = "HCN2, HCN4, KCNE2, long-QT syndrome 6, M54T mutation, MiRP1, pacemaker current, sinus bradycardia, sinus node dysfunction",
author = "Nawathe, {Pooja A.} and Yelena Kryukova and Oren, {Ronit V.} and Raffaella Milanesi and Clancy, {Colleen E} and Lu, {Jonathan T.} and Moss, {Arthur J.} and Dario Difrancesco and Robinson, {Richard B.}",
year = "2013",
month = "9",
doi = "10.1111/jce.12163",
language = "English (US)",
volume = "24",
pages = "1021--1027",
journal = "Journal of Cardiovascular Electrophysiology",
issn = "1045-3873",
publisher = "Wiley-Blackwell",
number = "9",

}

TY - JOUR

T1 - An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia

AU - Nawathe, Pooja A.

AU - Kryukova, Yelena

AU - Oren, Ronit V.

AU - Milanesi, Raffaella

AU - Clancy, Colleen E

AU - Lu, Jonathan T.

AU - Moss, Arthur J.

AU - Difrancesco, Dario

AU - Robinson, Richard B.

PY - 2013/9

Y1 - 2013/9

N2 - An LQTS6 M54T Mutation and Sinus Node Dysfunction Background Sinus 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. Objective We tested if LQTS6 incorporates sinus bradycardia due to abnormal If. Methods We 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. Results M54T 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. Conclusions We 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.

AB - An LQTS6 M54T Mutation and Sinus Node Dysfunction Background Sinus 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. Objective We tested if LQTS6 incorporates sinus bradycardia due to abnormal If. Methods We 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. Results M54T 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. Conclusions We 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.

KW - HCN2

KW - HCN4

KW - KCNE2

KW - long-QT syndrome 6

KW - M54T mutation

KW - MiRP1

KW - pacemaker current

KW - sinus bradycardia

KW - sinus node dysfunction

UR - http://www.scopus.com/inward/record.url?scp=84883802931&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84883802931&partnerID=8YFLogxK

U2 - 10.1111/jce.12163

DO - 10.1111/jce.12163

M3 - Article

C2 - 23631727

AN - SCOPUS:84883802931

VL - 24

SP - 1021

EP - 1027

JO - Journal of Cardiovascular Electrophysiology

JF - Journal of Cardiovascular Electrophysiology

SN - 1045-3873

IS - 9

ER -