Cyclase-associated proteins are highly con-
served proteins that have a role in the regulation of actin
dynamics. Higher eukaryotes have two isoforms, CAP1
and CAP2. To study the in vivo function of CAP2, we
generated mice in which the CAP2 gene was inactivated by
a gene-trap approach. Mutant mice showed a decrease in
body weight and had a decreased survival rate. Further,
they developed a severe cardiac defect marked by dilated
cardiomyopathy (DCM) associated with drastic reduction
in basal heart rate and prolongations in atrial and ventricular conduction times. Moreover, CAP2-deficient
myofibrils exhibited reduced cooperativity of calcium-
regulated force development. At the microscopic level, we
observed disarrayed sarcomeres with development of
fibrosis. We analyzed CAP2’s role in actin assembly and
found that it sequesters G-actin and efficiently fragments
filaments. This activity resides completely in its WASP
homology domain. Thus CAP2 is an essential component
of the myocardial sarcomere and is essential for physio-
logical functioning of the cardiac system, and a deficiency
leads to DCM and various cardiac defects.