title: Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy.
abstract: Cyclase-associated proteins are highly conserved 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 physiological functioning of the cardiac system, and a deficiency leads to DCM and various cardiac defects.
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Cologne, Germany.
authors.forename: Vivek S
authors.initials: VS
authors.lastname: Peche
authors.forename: Tad A
authors.initials: TA
authors.lastname: Holak
authors.forename: Bhagyashri D
authors.initials: BD
authors.lastname: Burgute
authors.forename: Kosmas
authors.initials: K
authors.lastname: Kosmas
authors.forename: Sushant P
authors.initials: SP
authors.lastname: Kale
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.forename: Fatiha
authors.initials: F
authors.lastname: Elhamine
authors.forename: Robert
authors.initials: R
authors.lastname: Stehle
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pfitzer
authors.forename: Klaus
authors.initials: K
authors.lastname: Nohroudi
authors.forename: Klaus
authors.initials: K
authors.lastname: Addicks
authors.forename: Florian
authors.initials: F
authors.lastname: Stöckigt
authors.forename: Jan W
authors.initials: JW
authors.lastname: Schrickel
authors.forename: Julia
authors.initials: J
authors.lastname: Gallinger
authors.forename: Michael
authors.initials: M
authors.lastname: Schleicher
authors.forename: Angelika A
authors.initials: AA
authors.lastname: Noegel
mesh_terms: D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D006321:Heart / Q000033:anatomy & histology / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012518:Sarcomeres / Q000378:metabolism; D008565:Membrane Proteins; D048868:Adaptor Proteins, Signal Transducing
chemical_list: D000199:Actins; D002118:Calcium; D002352:Carrier Proteins; C525400:Cap2 protein, mouse; D008565:Membrane Proteins; D048868:Adaptor Proteins, Signal Transducing