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 |