Digenic Heterozigosity in SCN5A and CACNA1C Explains the Variable Expressivity of the Long QT Phenotype in a Spanish Family

Nieto-Marín, Paloma; Jiménez‐Jáimez, Juan; Tinaquero, David; Alfayate, Silvia; Utrilla, Raquel G.; Rey, Maria del Mar Rodríguez Vázquez del; Perín, Francesca; Sarquella‐Brugada, Georgia; Monserrat, Lorenzo; Brugada, Josép; Tercedor, Luís; Tamargo, Juan; Delpón, Eva; Caballero, Ricardo

doi:10.1016/j.rec.2018.03.012

Cited by 5 publications

(5 citation statements)

References 33 publications

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“…Such variation would not be expected to co‐segregate with the major mutation; at least with respect to the 14 channel genes listed above, none are located on the same chromosome (number 12) as is CACNA1C . A similar but more palpable basis of reduced penetrance is proposed in Liu et al (), of a family in which some members carried a convincingly pathogenic mutation in another gene ( SCN5A ) which appeared to modulate the effects of a CACNA1C p.Q1916R variant, a scenario which these authors refer to as “digenic variation.” Similar pictures are recorded in Nieto‐Marín et al () and in Zhu, Luo, Jiang, and Liu (). Variation elsewhere in the same gene may not, however, necessarily have an effect, as Crotti et al () show with respect to the KCNQ1 (LQTS 1) variant.…”

Section: Discussionsupporting

confidence: 84%

Penetrance and expressivity of the R858H CACNA1C variant in a five‐generation pedigree segregating an arrhythmogenic channelopathy

Gardner

Crozier

Binfield

et al. 2018

Molec Gen & Gen Med

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Background Isolated cardiac arrhythmia due to a variant in CACNA1C is of recent knowledge. Most reports have been of singleton cases or of quite small families, and estimates of penetrance and expressivity have been difficult to obtain. We here describe a large pedigree, from which such estimates have been calculated. Methods We studied a five‐generation family, in which a CACNA1C variant c.2573G>A p.Arg858His co‐segregates with syncope and cardiac arrest, documenting electrocardiographic data and cardiac symptomatology. The reported patients/families from the literature with CACNA1C gene variants were reviewed, and genotype–phenotype correlations are drawn. Results The range of phenotype in the studied family is wide, from no apparent effect, through an asymptomatic QT interval prolongation on electrocardiography, to episodes of presyncope and syncope, ventricular fibrillation, and sudden death. QT prolongation showed inconsistent correlation with functional cardiology. Based upon analysis of 28 heterozygous family members, estimates of penetrance and expressivity are derived. Conclusions These estimates of penetrance and expressivity, for this specific variant, may be useful in clinical practice. Review of the literature indicates that individual CACNA1C variants have their own particular genotype–phenotype correlations. We suggest that, at least in respect of the particular variant reported here, “arrhythmogenic channelopathy” may be a more fitting nomenclature than long QT syndrome.

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Section: Discussionsupporting

confidence: 84%

Penetrance and expressivity of the R858H CACNA1C variant in a five‐generation pedigree segregating an arrhythmogenic channelopathy

Gardner

Crozier

Binfield

et al. 2018

Molec Gen & Gen Med

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“…[53]. Mutant human Nav1.5 currents containing either the N1325S, F1486L, ∆K1500, ∆KPQ (in-frame deletion of K1505/P1506/Q1507) or R1644H [33][34][35][36][37][38][39][40][41][42][43][44][45] where measure before and after the application of empagliflozin (10 µM). Empagliflozin inhibited late INa in all these class I LQT3 mutants residing in the inactivation gate (Figure 2).…”

Section: ) As Induction Of Latementioning

confidence: 99%

“…The vast majority of LQT3 cases are caused by autosomal dominant mutations in SCN5A, and they can be categorized into different classes based on their location within the channel. We designated class I mutations as those involved in inactivation gating between DIII and IV, and include N1325S, F1486L, ∆K1500, ∆KPQ (in-frame deletion of K1505, P1506, and Q1507), and R1644H [33][34][35][36][37][38][39][40][41][42][43][44][45]. Class II mutations were designated as those residing in the voltagesensing regions (S4 activation helices), which include R225Q, R1623Q, and R1626P [9; 46].…”

Section: Lqt3 Mutationsmentioning

confidence: 99%

The Sodium/Glucose Cotransporter 2 Inhibitor Empagliflozin Inhibits Long QT 3 Late Sodium Currents in a Mutation Specific Manner

Lunsonga,

Fatehi,

Long

et al. 2024

Preprint

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Background: Sodium/glucose cotransporter 2 inhibitors (SGLT2is) such as empagliflozin have demonstrated substantial cardioprotective effects in patients with or without diabetes. The SGLT2is have been shown to selectively inhibit the late component of cardiac sodium current (late INa). Induction of late INa is also the primary mechanism involved in the pathophysiology of congenital long QT syndrome type 3 (LQT3) gain-of-function mutations in the SCN5A gene that encodes the major cardiac sodium channel isoform Nav1.5. Therefore, we investigated the effect of empagliflozin on late INa in thirteen known LQT3 mutations located in distinct regions of the channel. Methods: The whole-cell patch-clamp technique was used to investigate the effect of empagliflozin (10 μM) on late INa in recombinantly expressed Nav1.5 channels containing different LQT3 mutations. Molecular modeling of human Nav1.5 and simulations in a mathematical model of human ventricular myocytes were used to extrapolate our experimental results to excitation contraction coupling. Results: Empagliflozin selectively inhibited late INa in LQT3 mutations residing in the inactivation gate region of Nav1.5, with no effect on either peak current or channel kinetics. In contrast, empagliflozin inhibited both peak and late INa in mutations in the S4 voltage-sensing regions as well as changes in activation and inactivation kinetics and a slowing of recovery from inactivation. Empagliflozin had no effect on late/peak INa or channel kinetics in channels containing LQT3 mutations located in the putative empagliflozin binding region. Simulation of our experimental findings in a mathematical model of human ventricular myocytes predicts that empagliflozin may have a desirable therapeutic effect in LQT3 mutations located in the inactivation gate region. Conclusions: Our results show that empagliflozin selectively inhibits late INa, without affecting gating kinetics, in LQT3 mutations residing in the inactivation gate region. The SGLT2is may therefore be a promising novel precision medicine approach for patients with certain LQT3 mutations.

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“…L-type calcium current is the primary inward current in the action potential plateau phase, while T-type calcium current depolarizes current in phase 0 of action potential duration [ 17 ]. Generated and conducted from the sinoatrial node and atrioventricular node, L-type Ca2+ current was not only the primary inward current in atrial and ventricular action potential 2 phases [ 18 ]. Depolarization of cardiomyocytes can open the L-type calcium channel and the influx of Ca2+ and then trigger the release of Ca2+ from the sarcoplasmic reticulum.…”

Section: Ion Channels and Connexins In The Pathogenesis Of Atrial Fib...mentioning

confidence: 99%

“…Tetrandrine dosage-dependently inhibited delayed rectifier potassium current. The maximum effective concentration is 3 × 10 −5 mol/L [ 18 ]. Tetrandrine had a bidirectional regulation effect on calcium-activated potassium channels.…”

Section: Natural Products With Bioactivity In Afmentioning

confidence: 99%

Research Progress on Natural Products’ Therapeutic Effects on Atrial Fibrillation by Regulating Ion Channels

Ding

et al. 2022

Cardiovascular Therapeutics

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Antiarrhythmic drugs (AADs) have a therapeutic effect on atrial fibrillation (AF) by regulating the function of ion channels. However, several adverse effects and high recurrence rates after drug withdrawal seriously affect patients’ medication compliance and clinical prognosis. Thus, safer and more effective drugs are urgently needed. Active components extracted from natural products are potential choices for AF therapy. Natural products like Panax notoginseng (Burk.) F.H. Chen, Sophora flavescens Ait., Stephania tetrandra S. Moore., Pueraria lobata (Willd.) Ohwi var. thomsonii (Benth.) Vaniot der Maesen., and Coptis chinensis Franch. have a long history in the treatment of arrhythmia, myocardial infarction, stroke, and heart failure in China. Based on the classification of chemical structures, this article discussed the natural product components’ therapeutic effects on atrial fibrillation by regulating ion channels, connexins, and expression of related genes, in order to provide a reference for development of therapeutic drugs for atrial fibrillation.

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Digenic Heterozigosity in SCN5A and CACNA1C Explains the Variable Expressivity of the Long QT Phenotype in a Spanish Family

Cited by 5 publications

References 33 publications

Penetrance and expressivity of the R858H CACNA1C variant in a five‐generation pedigree segregating an arrhythmogenic channelopathy

Penetrance and expressivity of the R858H CACNA1C variant in a five‐generation pedigree segregating an arrhythmogenic channelopathy

The Sodium/Glucose Cotransporter 2 Inhibitor Empagliflozin Inhibits Long QT 3 Late Sodium Currents in a Mutation Specific Manner

Research Progress on Natural Products’ Therapeutic Effects on Atrial Fibrillation by Regulating Ion Channels

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