Dominant negative consequences of a hERG 1b-specific mutation associated with intrauterine fetal death.

Progress in Biophysics and Molecular Biology
David K JonesGail A Robertson

Abstract

The human ether-a-go-go related gene (hERG) encodes two subunits, hERG 1a and hERG 1b, that combine in vivo to conduct the rapid delayed rectifier potassium current (IKr). Reduced IKr slows cardiac action potential (AP) repolarization and is an underlying cause of cardiac arrhythmias associated with long QT syndrome (LQTS). Although the physiological importance of hERG 1b has been elucidated, the effects of hERG 1b disease mutations on cardiac IKr and AP behavior have not been described. To explore the disease mechanism of a 1b-specific mutation associated with a case of intrauterine fetal death, we examined the effects of the 1b-R25W mutation on total protein, trafficking and membrane current levels in HEK293 cells at physiological temperatures. By all measures the 1b-R25W mutation conferred diminished expression, and exerted a temperature-sensitive, dominant-negative effect over the WT hERG 1a protein with which it was co-expressed. Membrane currents were reduced by 60% with no apparent effect on voltage dependence or deactivation kinetics. The dominant-negative effects of R25W were demonstrated in iPSC-CMs, where 1b-R25W transfection diminished native IKr compared to controls. R25W also slowed AP repolarization, and increase...Continue Reading

References

Jan 1, 1972·Cardiovascular Research·G E Freud
Jan 1, 1971·Pflügers Archiv : European journal of physiology·W Tuganowski, A Cekański
Jul 1, 1970·Acta Physiologica Scandinavica·G Gennser, E Nilsson
Aug 8, 1998·The Journal of Biological Chemistry·Z ZhouC T January
Jun 1, 2000·The Journal of General Physiology·J WangG A Robertson
Aug 12, 2004·The Journal of Biological Chemistry·Eugenia M C JonesGail A Robertson
Aug 3, 2007·Cardiovascular Research·David J GallacherPaul G A Volders
Feb 14, 2009·Circulation Research·Jianhua ZhangTimothy J Kamp
Jun 9, 2009·Biochemical and Biophysical Research Communications·M J McPateJ C Hancox
Nov 9, 2011·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Lisa L MurphyAlfred L George
Jun 30, 2012·Proceedings of the National Academy of Sciences of the United States of America·Hongkang ZhangMin Li
Feb 9, 2013·Circulation. Arrhythmia and Electrophysiology·Deborah K LieuRonald A Li
Apr 11, 2013·JAMA : the Journal of the American Medical Association·Lia CrottiMichael J Ackerman
Jul 24, 2013·The Journal of Physiology·Norbert JostStanley Nattel
Jan 11, 2014·Pflügers Archiv : European journal of physiology·Christina M HullTom W Claydon
Jul 31, 2014·The Journal of Biological Chemistry·Chai Ann NgMatthew D Perry
Sep 23, 2014·Heart Rhythm : the Official Journal of the Heart Rhythm Society·J Philip SaulJohn K Triedman
Nov 25, 2014·Nature Communications·Corey L AndersonCraig T January
Dec 3, 2014·Proceedings of the National Academy of Sciences of the United States of America·David K JonesGail A Robertson
Dec 30, 2015·Progress in Biophysics and Molecular Biology·Colin H PetersPeter C Ruben

❮ Previous
Next ❯

Citations

Jan 19, 2016·Progress in Biophysics and Molecular Biology·T Alexander Quinn, Crystal M Ripplinger
Dec 30, 2015·Progress in Biophysics and Molecular Biology·Colin H PetersPeter C Ruben
Nov 2, 2017·The Journal of Biological Chemistry·Beth A McNallyMatthew C Trudeau
May 1, 2018·Frontiers in Physiology·Laura L PerissinottiSergei Y Noskov
Jun 1, 2021·Journal of Pharmacological and Toxicological Methods·Erick B Ríos-PérezGail A Robertson
Jun 12, 2021·Heart Rhythm O2·Daniela Ponce-Balbuena, Isabelle Deschênes

❮ Previous
Next ❯

Related Concepts

Related Feeds

Bioinformatics in Biomedicine

Bioinformatics in biomedicine incorporates computer science, biology, chemistry, medicine, mathematics and statistics. Discover the latest research on bioinformatics in biomedicine here.

Atrial Fibrillation

Atrial fibrillation is a common arrhythmia that is associated with substantial morbidity and mortality, particularly due to stroke and thromboembolism. Here is the latest research.

Arrhythmia

Arrhythmias are abnormalities in heart rhythms, which can be either too fast or too slow. They can result from abnormalities of the initiation of an impulse or impulse conduction or a combination of both. Here is the latest research on arrhythmias.