CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy

Abstract

BackgroundDilated cardiomyopathy (DCM) is a primary myocardial disease leading to contractile dysfunction, progressive heart failure and excessive risk of sudden cardiac death. Around half of DCM cases are idiopathic, and genetic factors seem to play an important role.AimWe investigated a possible genetic cause of DCM in two consanguineous children from a Bedouin family.Methods and resultsUsing exome sequencing and searching for rare homozygous variations, we identified a nucleotide change in the donor splice consensus sequence of exon 7 in CAP2 as the causative mutation. Using patient-derived fibroblasts, we demonstrated that the mutation causes skipping of exons 6 and 7. The resulting protein is missing 64 amino acids in its N-CAP domain that should prevent its correct folding. CAP2 protein level was markedly reduced without notable compensation by the homolog CAP1. However, β-actin mRNA was elevated as demonstrated by real-time qPCR. In agreement with the essential role of CAP2 in actin filament polymerization, we demonstrate that the mutation affects the kinetics of repolymerization of actin in patient fibroblasts.ConclusionsThis is the first report of a recessive deleterious mutation in CAP2 and its association with DCM in humans. The clinical phenotype recapitulates the damaging effects on the heart observed in Cap2 knockout mice including DCM and cardiac conduction disease, but not the other effects on growth, viability, wound healing and eye development. Our data underscore the importance of the proper kinetics of actin polymerization for normal function of the human heart.

CAPt’n of Actin Dynamics: Recent Advances in the Molecular, Developmental and Physiological Functions of Cyclase-Associated Protein (CAP)

“…This study further reported that cardiac conduction defects can culminate in a complete heart block, which likely caused increased lethality of systemic and cardiomyocyte-specific mutants (Peche et al, 2012;Field et al, 2015). Of note, DCM and cardiac conduction defects have been recently associated with CAP2 mutations in humans (Aspit et al, 2019).…”

Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset

“…Comparison of the CAP2-KO and CAP2-CKO mice with human CAP2-DCM is in the early stages because only 2 patients have been described with homozygous CAP2 mutations (21). Their DCM was diagnosed at ages 5 and 12; the 12-year-old died shortly after diagnosis and was not completely phenotyped.…”

“…Both affected family members were the only ones in the pedigree having the same homozygous CAP2 mutation, while 12 heterozygotes had no evidence of DCM. Therefore, the CAP2 mutations segregate as an autosomal recessive DCM gene (21), though some mutations may be dominant or semidominant.…”

Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility

“…Furthermore, Aspit et al recently reported two children with DCM from a consanguineous Beduine family. Both patients had a homozygous variant affecting the donor splice site of CAP2 exon 7, which causes skipping of exons 6 and 7 in patient-derived fibroblasts 12 . Taking both studies into account, these findings strongly suggest a role of CAP2 in DCM and the importance of this gene for normal function of the human heart.…”