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Table 1 Pathogenic gene mutations associated with LQTS variants

From: Sudden cardiac death: focus on the genetics of channelopathies and cardiomyopathies

Mutated gene Encoded protein Functional alteration LQTS variant
KCNQ1 α-subunit of the voltage-gated potassium channel that mediates the slow component of the delayed rectifier potassium current (IKs) Reduction of IKs, with subsequent prolonged repolarization of the action potential [111,112,113] LQTS1
KCNH2 α-subunit of the voltage-gated potassium channel that mediates the rapidly activating component of the delayed rectifying potassium current (IKr) Reduction of IKr and delay in cardiac repolarization which leads to a prolonged QT interval [114] LQTS2
SCN5A α-subunit of the cardiac sodium channel Nav1.5 Gain-of-function. SCN5A variants induce an increased late inward Nav1.5 current, which slows cardiac repolarization and causes prolongation of the QT interval [115] LQTS3
ANK2 Ankyrin-B, a protein involved in the coordinated assembly of the Na+/K+ ATPase, the Na+/Ca2+ exchanger, and the inositol triphosphate receptor Calcium homeostasis impairment that prolongs repolarization [116] LQTS4
KCNE1 β-subunit of Mink Impairment of multimeric channel complex stability [117, 118] LQTS5
KCNE2 β-subunit of MiRP1 Impairment of multimeric channel complex stability [119] LQTS6
KCNJ2 Inward rectifier potassium channel Kir2.1 (IK1) Impaired potassium current [120] LQTS7
CACNA1C L-type calcium channel Impaired open-state voltage-dependent inactivation of the L-type calcium channel [121] LQTS8
CAV3 Caveolin-3, the main scaffolding protein of cardiac caveolae Gain-of-function increase in late sodium current [25] LQTS9
SCN4B β-subunit of the sodium channel Gain-of-function increase in late sodium current [122] LQTS10
AKAP9 Kinase-A anchor protein-9 Reduced interaction with KCNQ1 [123] LQTS11
SNTA1 α1-syntrophin protein Gain-of-function increase in late sodium current [124] LQTS12
KCNJ5 Cardiac G-protein-coupled inward rectifier potassium channel subtype 4 Ventricular repolarization abnormality resulting in the prolongation of corrected QT and QT-peak intervals [125] LQTS13
CALM1 Calmodulin, a protein involved in calcium-dependent inactivation of the L-type calcium channel and ryanodine channel stabilization, thus affecting overall intracellular calcium levels Disruption of calcium-ion binding to the protein [126] LQTS14
CALM2 Calmodulin Disruption of calcium-ion binding to the protein [127] LQTS15
CALM3 Calmodulin Disruption of calcium-ion binding to the protein [128] LQTS16
TRDN Triadin Impairment of cardiac calcium release that affects excitation-contraction coupling and leads to cardiac arrhythmias [34] LQTS16