Cardiac channelopathies: from men to mice

During recent years, genetic manipulations in the mouse aimed to settle animal models of cardiac channelopathies. Among this group of diseases, the genetically heterogeneous long-QT (LQT) syndrome has instigated several models. Models of the LQT1 syndrome have been obtained by invalidation of Kcnq1 encoding a voltage-dependent K+ channel alpha-subunit, LQT2 syndrome by invalidation of Merg also encoding a voltage-dependent K+ channel alpha-subunit, LQT3 by knocking-in a gain-of-function deletion (delta KPQ) of the Scn5A cardiac Na+ channel gene, LQT4 by invalidating the ankyrin B gene. LQT5 by invalidating the Kcne1 K+ channel beta-subunit and the Andersen syndrome by invalidation of the KCNJ2 gene encoding for a cardiac inward rectifier K+ channel. Among these LQT models, the LQT3 and LQT4 mice exhibit spontaneous or exercise-induced life-threatening arrhythmias characteristics of long-QT patients. In addition, a model for the SCN5A-linked Brugada syndrome and for the inherited Lenègre disease has been established by heterozygous knock-out of Scn5A. These mice demonstrate progressive cardiac conduction defect similar to that observed in Lenègre patients and an increased susceptibility to arrhythmias as found in Brugada patients. In the future, the mouse model should prove instrumental to investigate the myocardial remodeling that is likely to result from gene invalidation either in man or in mice.