title: A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy.
abstract: BACKGROUND
  Dilated cardiomyopathy (DCM) is a primary disease of the heart muscle associated with sudden cardiac death secondary to ventricular tachyarrhythmias and asystole. However, the molecular pathways linking DCM to arrhythmias and sudden cardiac death are unknown. We previously identified a S196L mutation in exon 4 of LBD3-encoded ZASP in a family with DCM and sudden cardiac death. These findings led us to hypothesize that this mutation may precipitate both cytoskeletal and conduction abnormalities in vivo. Therefore, we investigated the role of the ZASP4 mutation S196L in cardiac cytoarchitecture and ion channel biology.
  
  
  RESULTS
  We generated and analyzed transgenic mice with cardiac-restricted expression of the S196L mutation. We also performed cellular electrophysiological analysis on isolated S196L cardiomyocytes and protein-protein interaction studies. Ten month-old S196L mice developed hemodynamic dysfunction consistent with DCM, whereas 3-month-old S196L mice presented with cardiac conduction defects and atrioventricular block. Electrophysiological analysis on isolated S196L cardiomyocytes demonstrated that the L-type Ca(2+) currents and Na(+) currents were altered. The pull-down assay demonstrated that ZASP4 complexes with both calcium (Ca(v)1.2) and sodium (Na(v)1.5) channels.
  
  
  CONCLUSIONS
  Our findings provide new insight into the mechanisms by which mutations of a structural/cytoskeletal protein, such as ZASP, lead to cardiac functional and electric abnormalities. This work represents a novel framework to understand the development of conduction defects and arrhythmias in subjects with cardiomyopathies, including DCM.
authors.affiliation: Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Tex, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Li
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ai
authors.forename: Kaveh
authors.initials: K
authors.lastname: Samani
authors.forename: Yutao
authors.initials: Y
authors.lastname: Xi
authors.forename: Huei-Ping
authors.initials: HP
authors.lastname: Tzeng
authors.forename: Mingxing
authors.initials: M
authors.lastname: Xie
authors.forename: Shan
authors.initials: S
authors.lastname: Wu
authors.forename: Shuping
authors.initials: S
authors.lastname: Ge
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Jian-Wen
authors.initials: JW
authors.lastname: Dong
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sinagra
authors.forename: Luca
authors.initials: L
authors.lastname: Brunelli
authors.forename: Georgine
authors.initials: G
authors.lastname: Faulkner
authors.forename: Matteo
authors.initials: M
authors.lastname: Vatta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D003599:Cytoskeleton / Q000648:ultrastructure*; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D006329:Heart Conduction System / Q000503:physiopathology* / Q000648:ultrastructure; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D007150:Immunohistochemistry; D060588:LIM Domain Proteins; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009124:Muscle Proteins; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure*; D016133:Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C485639:Ldb3 protein, mouse; D009124:Muscle Proteins; D004247:DNA