P111SCN1Bb: a new susceptibly gene underlying LQT syndrome

SCN5A and SNTA1 are reported susceptible genes for long QT syndrome (LQTS). This study was designed to elucidate a plausible pathogenic arrhythmia mechanism for the combined novel mutations R800L-SCN5A and A261V-SNTA1 on cardiac sodium channels. A Caucasian family with syncope and marginally prolonged QT interval was screened for LQTS-susceptibility genes and found to harbor the R800L mutation in SCN5A and A261V mutation in SNTA1, and those with both mutations had the strongest clinical phenotype. The mutations were engineered into the most common splice variant of human SCN5A and SNTA1 cDNA, respectively, and sodium current ( INa) was characterized in human embryonic kidney 293 cells cotransfected with neuronal nitric oxide synthase (nNOS) and the cardiac isoform of the plasma membrane Ca-ATPase (PMCA4b). Peak INa densities were unchanged for wild-type (WT) and for mutant channels containing R800L-SCN5A, A261V-SNTA1, or R800L-SCN5A plus A261V-SNTA1. However, late INa for either single mutant was moderately increased two- to threefold compared with WT. The combined mutations of R800L-SCN5A plus A261V-SNTA1 significantly enhanced the INa late/peak ratio by 5.6-fold compared with WT. The time constants of current decay of combined mutant channel were markedly increased. The gain-of-function effect could be blocked by the NG-monomethyl-l-arginine, a nNOS inhibitor. We conclude that novel mutations in SCN5A and SNTA1 jointly exert a nNOS-dependent gain-of-function on SCN5A channels, which may consequently prolong the action potential duration and lead to LQTS phenotype.

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The study of the functionality of cardiomyocytes obtained from induced pluripotent stem cells for the modeling of cardiac arrhythmias based on long QT syndrome

Vavilov Journal of Genetics and Breeding ◽

10.18699/vj18.346 ◽

2018 ◽

Vol 22 (2) ◽

pp. 187-195 ◽

Cited By ~ 1

Author(s):

M. M. Slotvitsky ◽

V. A. Tsvelaya ◽

S. R. Frolova ◽

E. V. Dement’eva ◽

K. I. Agladze

Keyword(s):

Cardiac Tissue ◽

Single Cells ◽

Electrophysiological Study ◽

Heart Rhythm ◽

Cardiac Cells ◽

Long Qt ◽

Induced Pluripotent ◽

Physiological Values ◽

Relationship Of ◽

Lqt Syndrome

There are risk factors that lead the normal conduction of excitation in the heart into a chaotic one. These factors include hereditary and acquired channelopathies. Many dangerous changes in the work of the heart can be identified using the patient’s electrocardiogram. Such relatively easily detectable changes include the long QT interval syndrome (LQTS). Despite a relatively high prevalence of hereditary LQTS, to which it is necessary to add both hereditary and induced LQTS as well as the ease of detection on the ECG, the mechanism of reentry formation in this syndrome is still unknown. What should be noted is a high variability of the hereditary syndrome and the fact of the connection between the increase in the heart rate and the risk of cardiac arrest. After an electrophysiological study on individual cardiac cells from patients with the LQT syndrome, it became apparent that the search for a mechanism for the transition of the normal heart rhythm to chaotic and fibrillation cannot be limited to recording ion currents in single cells. To solve this problem, we need a model of the behavior of cardiac tissue which reflects the relationship of various factors and the risk of reentry. In order to create an experimental model of LQTS in our work, the iPSC of a patient-specific line from a healthy patient was differentiated into a monolayer of cardiac cells and the parameters of the excitation propagation were studied depending on the stage of differentiation. It was shown that a stable value of the propagation velocity and the response to periodic stimulation in the range of physiological values, are reached after the 30th day of differentiation.

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Mexiletine Treatment for Neonatal LQT3 Syndrome: Case Report and Literature Review

Frontiers in Pediatrics ◽

10.3389/fped.2021.674041 ◽

2021 ◽

Vol 9 ◽

Author(s):

Alena Bagkaki ◽

Alexandros Tsoutsinos ◽

Eleftheria Hatzidaki ◽

Manolis Tzatzarakis ◽

Fragiskos Parthenakis ◽

...

Keyword(s):

High Risk ◽

Literature Review ◽

Neonatal Period ◽

Positive Family History ◽

Clinical Importance ◽

Response To Treatment ◽

Specific Response ◽

Cardiac Events ◽

Type 3 ◽

Lqt Syndrome

Background: Early diagnosis of long QT type 3 (LQT3) syndrome during the neonatal period is of paramount clinical importance. LQT3 syndrome results in increased mortality and a mutation-specific response to treatment compared to other more common types of LQT syndrome. Mexiletine, a sodium channel blocker, demonstrates a mutation-specific QTc shortening effect in LQT3 syndrome patients.Case Presentation: A neonate manifested marked QTc prolongation after birth. An electrocardiogram (ECG) recording was performed due to positive family history of genetically confirmed LQT3 syndrome (SCN5A gene missense mutation Tyr1795Cys), and an association with sudden cardiac death was found in family members. The mexiletine QTc normalizing effect (QTc shortening from 537 to 443 ms), practical issues related to oral mexiletine treatment of our young patient, along with a literature review regarding identification and mexiletine treatment in infants with LQT3 syndrome are presented.Conclusions: Mexiletine could be considered in the treatment of high-risk LQT3 patients already in the neonatal period in addition to b-blocker therapy. Availability of standardized commercial mexiletine pediatric formulas, serum mexiletine level analyses, and future prospective studies are needed to evaluate the potential beneficial effect of early mexiletine treatment on the incidence of future acute cardiac events in these high-risk LQT syndrome patients.

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QT/RR dynamic coupling in LQT syndrome patients

Journal of Electrocardiology ◽

10.1016/j.jelectrocard.2013.05.096 ◽

2013 ◽

Vol 46 (4) ◽

pp. e26

Author(s):

P.L. Pavel Leinveber ◽

J.H. Josef Halamek ◽

J.P.C. Jean-Phillipe Couderc ◽

P.J. Pavel Jurak ◽

V.V. Vlastimil Vondra

Keyword(s):

Dynamic Coupling ◽

Lqt Syndrome

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The LQT-associated calmodulin mutant E141G induces disturbed Ca2+-dependent binding and a flickering gating mode of the CaV1.2 channel

AJP Cell Physiology ◽

10.1152/ajpcell.00019.2020 ◽

2020 ◽

Vol 318 (5) ◽

pp. C991-C1004

Author(s):

Jingyang Su ◽

Qinghua Gao ◽

Lifeng Yu ◽

Xuanxuan Sun ◽

Rui Feng ◽

...

Keyword(s):

Single Channel ◽

Missense Variant ◽

Inhibitory Effect ◽

Channel Activity ◽

Peptide Fragments ◽

Patch Clamp Technique ◽

Open Time ◽

Channel Opening ◽

Lqt Syndrome ◽

Calmodulin Mutant

Calmodulin (CaM) mutations are associated with congenital long QT (LQT) syndrome (LQTS), which may be related to the dysregulation of the cardiac-predominant Ca2+ channel isoform CaV1.2. Among various mutants, CaM-E141G was identified as a critical missense variant. However, the interaction of this CaM mutant with the CaV1.2 channel has not been determined. In this study, by utilizing a semiquantitative pull-down assay, we explored the interaction of CaM-E141G with CaM-binding peptide fragments of the CaV1.2 channel. Using the patch-clamp technique, we also investigated the electrophysiological effects of the mutant on CaV1.2 channel activity. We found that the maximum binding (Bmax) of CaM-E141G to the proximal COOH-terminal region, PreIQ-IQ, PreIQ, IQ, and NT (an NH2-terminal peptide) was decreased (by 17.71–59.26%) compared with that of wild-type CaM (CaM-WT). In particular, the Ca2+-dependent increase in Bmax became slower with the combination of CaM-E141G + PreIQ and IQ but faster in the case of NT. Functionally, CaM-WT and CaM-E141G at 500 nM Ca2+ decreased CaV1.2 channel activity to 24.88% and 55.99%, respectively, compared with 100 nM Ca2+, showing that the inhibitory effect was attenuated in CaM-E141G. The mean open time of the CaV1.2 channel was increased, and the number of blank traces with no channel opening was significantly decreased. Overall, CaM-E141G exhibits disrupted binding with the CaV1.2 channel and induces a flickering gating mode, which may result in the dysfunction of the CaV1.2 channel and, thus, the development of LQTS. The present study is the first to investigate the detailed binding properties and single-channel gating mode induced by the interaction of CaM-E141G with the CaV1.2 channel.

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