Abstract
Calcium regulation plays a central role in cardiac function. Several variants in the calcium channel Cav1.2 have been implicated in arrhythmic syndromes. We screened patients with Brugada syndrome, short QT syndrome, early repolarisation syndrome, and idiopathic ventricular fibrillation to determine the frequency and pathogenicity of Cav1.2 variants. Cav1.2 related genes, CACNA1C, CACNB2 and CACNA2D1, were screened in 65 probands. Missense variants were introduced in the Cav1.2 alpha subunit plasmid by mutagenesis to assess their pathogenicity using patch clamp approaches. Six missense variants were identified in CACNA1C in five individuals. Five of them, A1648T, A1689T, G1795R, R1973Q, C1992F, showed no major alterations of the channel function. The sixth C-terminal variant, Cavα1c-T1787M, present mostly in the African population, was identified in two patients with resuscitated cardiac arrest. The first patient originated from Cameroon and the second was an inhabitant of La Reunion Island with idiopathic ventricular fibrillation originating from Purkinje tissues. Patch-clamp analysis revealed that Cavα1c-T1787M reduces the calcium and barium currents by increasing the auto-inhibition mediated by the C-terminal part and increases the voltage-dependent inhibition. We identified a loss-of-function variant, Cavα1c-T1787M, present in 0.8% of the African population, as a new risk factor for ventricular arrhythmia.
Highlights
Cardiac channelopathies are genetic disorders associated with an increased risk of ventricular arrhythmia and sudden death (SD) in young individuals with a structurally normal heart
Loss-of-function variants often associated with a shortening of the plateau phase of the action potential in the three Cav1.2 subunits have been reported in patients with Brugada syndrome (BrS) with or without short QT21,22, ERS23, SQTS24, and sudden unexplained death in the young (SUDY)[22,25,26]
In addition to frequent polymorphisms (MAF > 1% in all populations), we identified a number of less frequent missense variants of unknown significance (VUS) in the coding sequence of CACNA1C in patients affected by BrS, early repolarisation syndrome (ERS) or idiopathic ventricular fibrillation (IVF)
Summary
Cardiac channelopathies are genetic disorders associated with an increased risk of ventricular arrhythmia and sudden death (SD) in young individuals with a structurally normal heart. Missense variants localised at the C-terminal end of DI-S6 induce a nearly complete loss of Cav1.2 voltage-dependent inactivation (VDI) and prolongation of the plateau phase of cardiac action potential while others variants identified in the DIII-DIV loop induced a gain-of-function by increasing the “window” current[19]. Different molecular mechanisms were described, such as reduced current density due to impaired channel trafficking for the Cavα1c-A39V21, activation or inactivation curve shifts for Cavβ2b-S481L21 and SQTS-Cavα2δ1-S755T24 or a marked increase in Cav1.2 inactivation rate for Cavβ2b-T11I27. These variants have been associated with phase 2 re-entry[28,29] or focal activation/re-entry from/ within the Purkinje fibres[30]. We sought to identify new variants of Cav1.2 genes in a cohort of 65 patients, affected by inherited arrhythmia syndrome potentially related to calcium handling and to elucidate their functional consequences
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