Short QT syndrome (SQTS) emerged as a new inherited channelopathy characterized by constantly short QT interval (QTc<360ms) associated with atrial fibrillation, syncopal episodes, and/or sudden cardiac death in patients with no underlying structural heart disease. It has been associated with a gain of function in 3 distinct potassium channels (KCNH2, KCNQ1, and KCNJ2) or a loss-of-function of a calcium channel Cav1.2. We identified a 6-year-old male proband who experienced a syncope episode and presented a QTc of 346ms. In addition, a triangular T wave was observed in V2, V3 leads. His 34-year-old mother was also symptomatic (QTc: 359 ms), with Ventricular fibrillation. The grandmother was asymptomatic (QT: 405ms). After a screen for ion channel mutations, we found a variant of CACNA1C, gene encoding the ⍺1c of the cardiac L-type calcium channel, leading to c.667G>C transition caused a p.A223P substitution of a mammalian highly conserved residue. This variant was absent in 312 healthy controls.
Cardiac Ca2+ channels are complexes including ⍺1,β, and ⍺2δ subunits allowing the Ca2+ influx (ICaL) essential for excitationcontraction coupling. To evaluate the incidence of this substitution on Cav1.2 function,⍺1c,β2a, and ⍺2δ1b rat subunits were transfected in HEK-tsA201 cells. The human A223P mutation corresponds to A253P in the rat sequence. Whole-cell patch-clamp experiments were performed to study the mutation effects on ICaL biophysical parameters. A253P Cav1.2 generated a reduced ICaL (-5.48±0.85Pa/ pF, n=54) in comparison with WT Cav1.2 (−12.24±1.54Pa/pF, n=51). The voltage dependence of the Ca2+ current activation did not show any change (V1/2act: −11.54±1.15mV, n=9, versus −12.94±1.03mV, n=19 ; slope: 6.37±0.28mV versus 6.46±0.27mV, for mutant and WT channels, respectively). Second, we studied WT and mutant Cav1.2 expression levels. We quantified channels expression by Western blot. The mutated protein was expressed at the same level as WT-Cav1.2. We are currently investigating Cav1.2 addressing to the membrane. In conclusion, we have shown that A253P mutation reduces the ICaL amplitude but the mechanism behind this loss of function remains to be determined.Le texte complet de cet article est disponible en PDF.