Elucidation of the pathogenesis in long QT syndrome caused by a CALM2 variant, p.D134H, using knock-in mouse model

Long QT syndrome (LQTS) is an inherited arrhythmia syndrome leading to lethal arrhythmias in young people. The major cause of LQTS is pathogenic variants in genes encoding potassium or sodium channel. Recently, pathogenic variants in genes encoding calmodulin (CALM1-3) have been reported as an important cause of LQTS with severe phenotype. Although the pathogenesis of LQTS caused by variants in ion channel related genes had been clarified, calmodulins-related cause is still unknown.

We aimed to elucidate the phenotype of Calm2 D134H knock-in mice model.

We constructed a knock-in mouse model with Calm2 D134H (DH) and evaluated its electrophysiological characteristics. We recorded electrocardiography in 17-week-old wild-type (WT) (n=7) and DH (n=7) male mice. DH mice showed longer QT and corrected QT (QTc) than those in WT (QT 63.17 vs 42.18 ms, P=0.002, QTc 49.92 vs 45.4 ms, P=0.002). In addition, the heart rate of DH mice (418 bpm) are lower than that of WT (520 bpm) (P=0.003), which is a specific character in LQTS. In the arrhythmia induction by epinephrine and caffeine administration, DH mice showed more prominent QT prolongation than WT (QT 72.48 vs 49.29, QTc 58.09 vs 47.17 ms). During arrhythmia induction, two out of 7 DH mice died suddenly due to the ventricular fibrillation (VF), which was not observed in WT.

We for the first time generated and analyzed knock-in mouse model with Calm2 D134H and found the model is compatible with LQTS. Our mouse model would be useful to elucidate the pathogenesis of LQTS caused by CALM2 variants and the development of effective medications.