Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.
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.
Vatta
Matteo
M
Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, Texas, USA.
Mohapatra
Bhagyalaxmi
B
Jimenez
Shinawe
S
Sanchez
Ximena
X
Faulkner
Georgine
G
Perles
Zeev
Z
Sinagra
Gianfranco
G
Lin
Jiuann-Huey
JH
Vu
Thuy M
TM
Zhou
Qiang
Q
Bowles
Karla R
KR
Di Lenarda
Andrea
A
Schimmenti
Lisa
L
Fox
Michelle
M
Chrisco
Michelle A
MA
Murphy
Ross T
RT
McKenna
William
W
Elliott
Perry
P
Bowles
Neil E
NE
Chen
Ju
J
Valle
Giorgio
G
Towbin
Jeffrey A
JA
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*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018398:Homeodomain Proteins; C120696:LDB3 protein, human; D060588:LIM Domain Proteins; D009124:Muscle Proteins