title: Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
abstract: OBJECTIVE
  We evaluated the role of Cypher/ZASP in the pathogenesis of dilated cardiomyopathy (DCM) with or without isolated non-compaction of the left ventricular myocardium (INLVM).
  
  
  BACKGROUND
  Dilated cardiomyopathy, characterized by left ventricular dilation and systolic dysfunction with signs of heart failure, is genetically transmitted in 30% to 40% of cases. Genetic heterogeneity has been identified with mutations in multiple cytoskeletal and sarcomeric genes causing the phenotype. In addition, INLVM with a hypertrophic dilated left ventricle, ventricular dysfunction, and deep trabeculations, is also inherited, and the genes identified to date differ from those causing DCM. Cypher/ZASP is a newly identified gene encoding a protein that is a component of the Z-line in both skeletal and cardiac muscle.
  
  
  METHODS
  Diagnosis of DCM was performed by echocardiogram, electrocardiogram, and physical examination. In addition, levels of the muscular isoform of creatine kinase were measured to evaluate for skeletal muscle involvement. Cypher/ZASP was screened by denaturing high performance liquid chromatography (DHPLC) and direct deoxyribonucleic acid sequencing.
  
  
  RESULTS
  We identified and screened 100 probands with left ventricular dysfunction. Five mutations in six probands (6% of cases) were identified in patients with familial or sporadic DCM or INLVM. In vitro studies showed cytoskeleton disarray in cells transfected with mutated Cypher/ZASP.
  
  
  CONCLUSIONS
  These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and identify a mechanistic basis.
authors.affiliation: Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Vatta
authors.forename: Bhagyalaxmi
authors.initials: B
authors.lastname: Mohapatra
authors.forename: Shinawe
authors.initials: S
authors.lastname: Jimenez
authors.forename: Ximena
authors.initials: X
authors.lastname: Sanchez
authors.forename: Georgine
authors.initials: G
authors.lastname: Faulkner
authors.forename: Zeev
authors.initials: Z
authors.lastname: Perles
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sinagra
authors.forename: Jiuann-Huey
authors.initials: JH
authors.lastname: Lin
authors.forename: Thuy M
authors.initials: TM
authors.lastname: Vu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
authors.forename: Karla R
authors.initials: KR
authors.lastname: Bowles
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Lenarda
authors.forename: Lisa
authors.initials: L
authors.lastname: Schimmenti
authors.forename: Michelle
authors.initials: M
authors.lastname: Fox
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Chrisco
authors.forename: Ross T
authors.initials: RT
authors.lastname: Murphy
authors.forename: William
authors.initials: W
authors.lastname: McKenna
authors.forename: Perry
authors.initials: P
authors.lastname: Elliott
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bowles
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Giorgio
authors.initials: G
authors.lastname: Valle
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015152:Blotting, Northern; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D004452:Echocardiography; D006352:Heart Ventricles / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D060588:LIM Domain Proteins; D009124:Muscle Proteins / Q000235:genetics*; D016296:Mutagenesis; D009154:Mutation; D014162:Transfection; D018487:Ventricular Dysfunction, Left / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018398:Homeodomain Proteins; C120696:LDB3 protein, human; D060588:LIM Domain Proteins; D009124:Muscle Proteins