A novel LQT-3 mutation disrupts an inactivation gate complex with distinct rate-dependent phenotypic consequences.

Channels
John R BankstonRobert S Kass

Abstract

Inherited mutations of SCN5A, the gene that encodes Na(V)1.5, the alpha subunit of the principle voltage-gated Na(+) channel in the heart, cause congenital Long QT Syndrome variant 3 (LQT-3) by perturbation of channel inactivation. LQT-3 mutations induce small, but aberrant, inward current that prolongs the ventricular action potential and subjects mutation carriers to arrhythmia risk dictated in part by the biophysical consequences of the mutations. Most previously investigated LQT-3 mutations are associated with increased arrhythmia risk during rest or sleep. Here we report a novel LQT-3 mutation discovered in a pediatric proband diagnosed with LQTS but who experienced cardiac events during periods of mild exercise as well as rest. The mutation, which changes a single amino acid (S1904L) in the Na(V)1.5 carboxy terminal domain, disrupts the channel inactivation gate complex and promotes late Na(+) channel currents, not by promoting a bursting mode of gating, but by increasing the propensity of the channel to reopen during prolonged depolarization. Incorporating a modified version of the Markov model of the Na(V)1.5 channel into a mathematical model of the human ventricular action potential predicts that the biophysical conseq...Continue Reading

Citations

Mar 20, 2012·Nature Communications·Ian W GlaaserRobert S Kass
Jul 29, 2015·Channels·Sandra B GabelliL Mario Amzel
Mar 31, 2012·Pediatric Cardiology·Weihua Song, Weinian Shou
Oct 29, 2009·Human Mutation·Paula L HedleyMichael Christiansen
Jul 25, 2017·The Journal of Physiology·Mena AbdelsayedPeter C Ruben
Jan 2, 2013·The Journal of General Physiology·Cecile TerrenoireRobert S Kass
Feb 15, 2012·Proceedings of the National Academy of Sciences of the United States of America·Maen F SarhanChristopher A Ahern
Oct 27, 2018·Frontiers in Physiology·Wenjia LiAijun Sun
Oct 27, 2018·Nature Reviews. Cardiology·Steven A NiedererNatalia A Trayanova
Nov 4, 2016·Physiological Reviews·M S BohnenR S Kass
Feb 28, 2018·Scientific Reports·Mena AbdelsayedPeter C Ruben
May 11, 2019·Proceedings of the National Academy of Sciences of the United States of America·Bernd R GardillFilip Van Petegem
Dec 12, 2020·The Journal of General Physiology·Sara NathanL Mario Amzel
Dec 21, 2010·Journal of Molecular Biology·Benjamin Chagot, Walter J Chazin
May 23, 2021·Proceedings of the National Academy of Sciences of the United States of America·Po Wei KangManu Ben-Johny
Jun 12, 2021·Heart Rhythm O2·Daniela Ponce-Balbuena, Isabelle Deschênes
Oct 14, 2021·Biochemical Society Transactions·Samantha C SalvageChristopher L-H Huang

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