title: CAP2 in cardiac conduction, sudden cardiac death and eye development.
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.
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Field
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.
authors.forename: Diana Z
authors.initials: DZ
authors.lastname: Ye
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.
authors.forename: Manasi
authors.initials: M
authors.lastname: Shinde
authors.affiliation: Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.|Section of Cardiac Electrophysiology, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Schillinger
authors.affiliation: Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.
authors.forename: MinMin
authors.initials: M
authors.lastname: Lu
authors.affiliation: Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Skettini
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: University Laboratory Animal Resources and School of Veterinary Medicine, Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Brice
authors.affiliation: Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Pennsylvania 19041 USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chung
authors.affiliation: Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.|Section of Cardiac Electrophysiology, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.
authors.forename: Vickas V
authors.initials: VV
authors.lastname: Patel
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004562:Electrocardiography; D005123:Eye / Q000196:embryology* / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006329:Heart Conduction System / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008850:Microphthalmos / Q000235:genetics / Q000473:pathology; D009154:Mutation; D038081:Organogenesis / Q000235:genetics*; D010641:Phenotype; D008565:Membrane Proteins; D048868:Adaptor Proteins, Signal Transducing
chemical_list: D002352:Carrier Proteins; C525400:Cap2 protein, mouse; D008565:Membrane Proteins; D048868:Adaptor Proteins, Signal Transducing