CALMing Down Arrhythmogenic Calmodulinopathies via a Precision Medicine Approach

In this issue, Limpitikul et al used the novel CRISPR interference (CRSPRi) strategy to suppress the expression of an arrhythmogenic mutant calmodulin (CaM) gene in human induced pluripotent cell-derived cardiomyocytes (iPSC-CM). This mutant CaM (D130G) is linked with long-QT syndrome (LQTS). The main LQTS mechanism is via a loss in Ca affinity of CaM, resulting in a loss of Ca-dependent inactivation of L-type Ca current (I Ca ) and hence prolongation of the ventricular action potential duration (Figure). Several other human CaM mutations have been linked with LQTS and seem likely to function at I Ca in the same way (D96V, N98I, A103V, D130V, D134H, E141G, F142L). Indeed, all of these mutations are in the third and fourth Ca binding domains of CaM, which are known to be critical in I Ca inactivation. Human CaM mutations have also been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), a phenotype that is mediated by inappropriate diastolic SR Ca release channel (ryanodine receptor 2 [RyR2]) activity (CaM-N54I, N98S, and A103V) and also by the promotion of late Na current (I NaL ; CaM-141G) and some degree of target overlap exists. For example, N98S and A103V promote both I Ca and RyR2-mediated Ca leak, and E141G has effects on both I Ca and I NaL . Given the ubiquitous role of CaM in cellular Ca-dependent signaling, this is likely to be only the tip of the iceberg for CaM mutant effects, albeit highly apparent because of the strong arrhythmogenic phenotype. Many other CaM-signaling pathways might also be altered by human CaM mutations, but direct linkages have yet to be made (and may be more challenging to demonstrate).