Human Molecular Genetics Advance Access published online on November 21, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn400
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Cardiac-specific ablation of cypher leads to a severe form of dilated cardiomyopathy with premature death
1 Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA 2 Institute of Molecular Medicine, Peking University, Beijing 100871, China 3 Dulbecco Telethon Institute at Istituto di Tecnologie Biomediche (ITB) – Consiglio nazionale delle ricerche (CNR) (CNR), Via Fratelli Cervi 93, 20090 Segrate, Milan, Italy 4 Istituti di ricovero e cura a carattere scientifico (IRCCS) Multimedia, Scientific and Technology Pole, Via Fantoli 16/15, 20138, Milan, Italy
* Corresponding author: Ju Chen, Ph.D., Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, Tel: (858) 822-4276; Fax: (858) 822-1355, juchen{at}ucsd.edu
Received October 9, 2008; Accepted November 19, 2008
Accumulating data suggest a link between alterations/deficiencies in cytoskeletal proteins and the progression of cardiomyopathy and heart failure, although the molecular basis for this link remains unclear. Cypher/ZASP is a cytoskeletal protein localized in the sarcomeric Z-line. Mutations in its encoding gene have been identified in patients with isolated noncompaction of the left ventricular myocardium (INLVM), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM). To explore the role of Cypher in the myocardium and better understand the molecular mechanisms by which mutations in cypher cause cardiomyopathy, we utilized a conditional approach to knockout Cypher specifically in developing and adult myocardium. Cardiac-specific Cypher knockout mice developed a severe form of dilated cardiomyopathy with disrupted cardiomyocyte ultrastructure and decreased cardiac function, which eventually led to death before 23 weeks of age. A similar phenotype was observed in inducible cardiac-specific Cypher knockout mice in which Cypher was specifically ablated in adult myocardium. In both cardiac-specific Cypher knockout models, ERK and Stat3 signaling pathways were augmented. Finally, we demonstrate the specific binding of Cypher's PDZ domain to the C-terminal region of both calsarcin-1 and myotilin within the Z-line. In conclusion, our studies suggest that (i) Cypher plays a pivotal role in maintaining adult cardiac structure and cardiac function through protein-protein interactions with other Z-line proteins, (ii) myocardial ablation of Cypher results in DCM with premature death, and (iii) specific signaling pathways participate in Cypher mutant mediated dysfunction of the heart, and may in concert facilitate the progression to heart failure.
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