CALM1, CALM2, and CALM3 expression and translation efficiency provide insight into the severity of calmodulinopathy

Missense variants in the CALM1, CALM2, and CALM3 genes cause calmodulinopathy, which is characterized by ventricular arrhythmias and sudden cardiac death. Although the three genes encode an identical protein, their individual roles and gene-specific clinical implications remain poorly understood. We aimed to determine the relative contribution from each of the genes to the total calmodulin amount and assess the consequence of missense mutations on the severity of calmodulinopathy.

Using data from the Genotype-Tissue Expression (GTEx) project, we show that CALM2 constituted a higher percentage of the calmodulin-coding mRNA (41.9%) compared with CALM1 (36.8%) and CALM3 (21.3%) (P < 2 × 10-16). Paired RNA sequencing and ribosome profiling data from the left ventricle was used to demonstrate that the translation into calmodulin protein was significantly different among CALM1 (44.8%) and CALM2 (44.2%), and CALM3 (11.0%) (P < 2 × 10-16). The observed-to-expected ratio for the number of missense variants in the Genome Aggregation Database (gnomAD) was 0.29 (90% CI, 0.23-0.36) in CALM3, 0.20 (90% CI, 0.15-0.27) in CALM2, and 0.11 in CALM1 (90% CI, 0.07-0.17). In the International Calmodulinopathy Registry, a different percentage of carriers experiencing cardiac events was observed among those with missense variants in CALM1 (46/52, 89%), CALM2 (37/53, 70%), and CALM3 (20/35, 57%) (P = 0.004).

Compared with CALM1 and CALM2, CALM3 is under less negative selection and missense variant carriers are less prone to cardiac events. We suggest this is partially due to CALM3 accounting for only 11% of the calmodulin protein produced in the ventricles.