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 non-compaction of 
the left ventricular myocardium, dilated cardiomyopathy (DCM) and hypertrophic 
cardiomyopathy. To explore the role of Cypher in myocardium and to better 
understand molecular mechanisms by which mutations in cypher cause 
cardiomyopathy, we utilized a conditional approach to knockout Cypher, specially 
in either developing or adult myocardium. Cardiac-specific Cypher knockout (CKO) 
mice developed a severe form of DCM 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 CKO mice in 
which Cypher was specifically ablated in adult myocardium. In both 
cardiac-specific CKO 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.