Key result
Calm2 D134H mutation prolongs QTc intervals and triggers fatal VF in ~29% of mice.
Why the study?
Pathogenic variants in calmodulin genes cause severe LQTS, but the underlying pathogenesis remains unknown.
Does the Calm2 D134H knock-in mutation cause long QT syndrome phenotypes in a mouse model?
Does the Calm2 D134H knock-in mutation cause long QT syndrome phenotypes in a mouse model?
The Calm2 D134H knock-in mouse model successfully recapitulates the long QT syndrome phenotype, including QT prolongation and susceptibility to fatal ventricular fibrillation.
No immediate clinical implications; leaves open translation of Calm2 D134H LQTS modeling to humans.
Background 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. Purpose We aimed to elucidate the phenotype of Calm2 D134H knock-in mice model. Methods and Results 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. Conclusions 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.
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Amin et al. (2025) studied Long QT syndrome (n=14). Calm2 D134H knock-in vs. Wild-type mice was evaluated on QT interval (p=0.002). Calm2 D134H knock-in mice exhibited significantly longer QT (63.17 vs 42.18 ms, P=0.002) and QTc intervals compared to wild-type mice, along with lower heart rates and susceptibility to VF.
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