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Abstract
Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that confers a risk for sudden cardiac death, cardiac conduction disease, and a newly described developmental disorder (6p22 syndrome) is located at 6p22. One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics. To determine the role of CAP2 in vivo, we generated knockout (KO) mice. cap2−/cap2− males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2−/cap2− females survived at close to the expected levels and lived normal life spans. CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease. The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males. To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes. We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias. These studies establish a direct role for CAP2 and actin dynamics in sudden cardiac death and cardiac conduction disease.
Highlights
Anterior eye chamber abnormalities, hearing loss, ear abnormalities, micrognathia, hypotonia and heart defects[12,13,14,15]
The cytoskeleton is assembled by polymerization of globular actin (G-actin) monomers into filamentous actin (F-actin)
We tested the expression of CAP2 in heart, muscle and brain on western blots probed with a polyclonal antibody (Fig. 1c; data not shown for brain)
Summary
Anterior eye chamber abnormalities, hearing loss, ear abnormalities, micrognathia, hypotonia and heart defects[12,13,14,15]. CAP2 is part of the actin cytoskeleton, which regulates cell shape, cell motility and muscle contraction. All CAP homologs regulate the cytoskeleton by binding G-actin and cofilin[22,23]. Microinjection of antibodies suggested a role for CAP1 in regulating actin filaments[24] and knocking down CAP1 causes extensive actin filaments that turn over slowly[25]. The effects of CAP on filament turnover require cofilin, which directly accelerates actin filament turnover. CAP has little effect on filament turnover in vitro, it accelerates cofilin-promoted turnover and filament severing[26,27,28,29]. In C. elegans, CAP mutations cause defects in sarcomeric actin organization[32] and knockdown of CAP2 in zebrafish causes a short-body phenotype and pericardial edema[33]. Since at least one of the two CAP isoforms is expressed in most cells, it is likely that CAP1 and CAP2 complement each other in some cellular functions, but CAP2 may have unique roles, especially in skeletal and cardiac muscles[25,34]
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