Understanding Calmodulinopathies in an Animal Model

Sudden cardiac death (SCD) affects nearly 400,000 people each year, making it the largest cause of death in the United States. Although SCD is more prevalent in the elderly population, approximately 1,000-5,000 SCD cases occur in children and young adults under the age of 35 years and dramatically reduce the expected life-years of affected individuals. An underlying inherited structural or heart rhythm disorder may potentiate the risk of sudden cardiac arrest (SCA) and SCD in the young (SCDY). Long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are two genetic disorders of abnormal heart rhythm that occur in the young. Patients suspected of arrhythmia phenotypes are initially screened for mutations in known LQTS and CPVT susceptibility genes to elucidate the causality for such phenotypes. However, the cause for many cases are not discovered by this candidate gene approach. The development of exome sequencing provides a new approach to the study of SCD and unexplained death, and the opportunity to discover novel, de novo mutations that were once unknown. Using this technology, exome sequencing has been known to discover mutations found in one of three distinct genes (CALM1, CALM2, or CALM3) encoding an identical calcium sensing protein, calmodulin (CaM), that are associated with increased risk of arrhythmia phenotypes and SCDY. Most CaM mutations induce lower binding affinity of Ca2+ to the carboxyl-terminal domain of CaM. Impaired Ca2+ binding to CaM results in altered regulation of L-type Ca2+ channels (LTCC) and/or the ryanodine receptor (RYR2) responsible for intracellular Ca2+ release. These cellular mechanisms correlate with common clinical LQTS- and CPVT-like calmodulinopathy phenotypes, respectively. Although mechanisms have been proposed, there may be some mechanistic overlap or novel arrhythmogenic pathways that contribute to genotype-phenotype heterogeneity within the calmodulinopathy spectrum. The recurrent mutation CaM-N98S, which occurs in either CALM1 or CALM2, has been associated with both LQTS and CPVT arrhythmia phenotypes for reasons yet unknown. Understanding the mechanistic effects of CaM-N98S in an animal model may reveal crucial information for establishing a genotype-phenotype relationship of these calmodulinopathies. The lack of consistent phenotypes in subjects that are CaM N98S-positive drives our hypothesis that additional genetic factors influence phenotype selectivity.