attribué à Mohamed-Yassine Amarouch

A novel familial cardiac arrhythmia associated with a dilated cardiomyopathy is due to a mutation in SCN5A

Mohamed-Yassine Amarouch (Equipe Ic)
Lauréat d'un prix poster du GRRC-SFC 2010
Résumé de ses travaux récompensés :
Voltage-dependent cardiac sodium channels are complexes including and subunits allowing sodium influx during the depolarization phase of the ventricular action potential. The main pore-forming subunit, Nav1.5, is encoded by SCN5A. Using a candidate-gene approach, we detected a R222Q substitution in Nav1.5 in a family comprising 10 members affected by a new cardiac phenotype. Affected patients had a chaotic surface ECG displaying rare sinus or junctional beats competing with numerous premature ventricular contractions with various right bundle branch block patterns and right to left axis variations. Arrhythmia mechanisms involved ectopic foci originating from the Purkinje system. To evaluate the incidence of this substitution on Nav1.5 channel function, whole-cell patch-clamp experiments were performed on COS-7 cells transfected with the human and 1 subunits. The presence of the mutation did not modify the Na^+ current density. In contrast, the channel activation curve was shifted toward more negative potentials. Activation kinetics were also accelerated in mutant homozygous condition only. Inactivation voltage sensitivity was also changed and inactivation kinetics accelerated. Finally, recovery from inactivation was not modified by the R222Q mutation. We studied the impact of the current biophysical changes in virtual models of the Purkinje and ventricular action potentials. The premature ventricular contractions were explained by the appearance of electrical abnormalities in Purkinje and not in ventricular model, consistent with the ectopic foci originating from the conducting tissue.