Cypher and its close homologue, ENH contain a single N-terminal PDZ domain as well as three C-terminal LIM domains. Both Cypher and ENH deficient mice display cardiomyopathy. Many mutations in the human Cypher/Zasp gene have been indentified in patients with different forms of cardiomyopathy. Recently, Cypher mutations were also found in a portion of patients with myofibrillar myopathy, termed "Zaspopathy". We have characterized multiple splice isoforms of Cypher and ENH, which include short and long subtypes. An N-terminal PDZ domain is common to both short and long isoforms, whereas three LIM domains are unique to long isoforms. Cypher and ENH interact with the C-termini of Z-line proteins a-actinin, Calsarcin-1 and Myotilin, through their PDZ domains. Our preliminary data also show that Cypher long isoforms, but not Cypher short isoforms, interact with b1 integrin via the C-terminal LIM domains. We have also shown that mice null for Cypher long isoforms (CypherL-/-) develop cardiomyopathy and experience premature mortality, while mice null for Cypher short isoforms (CypherS-/-) appear phenotypically normal. To further understand potential roles of Cypher and ENH in heart, we are studying interactions between Cypher and ENH by generating and studying mice which are doubly null for Cypher and ENH (ENH-/-;Cypher-/-). ENH-/-;Cypher-/- mice die around embryonic day (E) 10.5 with an abnormal cardiac phenotype. Although ENH-null;Cypher heterozygous compound mutants (ENH-/-;Cypher) survive postnatally, the foregoing results suggest that these mutants are likely to exhibit a more severe DCM than ENH-/- mice alone. Also, while we have found that ENH-/-;CypherL-/- mutants die before birth, ENH-/-;CypherS-/- mutants survive postnatally. The foregoing results have led us to the hypothesis that Cypher is a critical linker protein both at the Z- line and at the costamere, via its interactions with a-actinin 2, Calsarcin, Myotilin, and b1 integrin. Furthermore, we suggest that Cypher and ENH have redundant, yet unique, roles in cardiac development and function. The overall goals of this proposal are to understand the role of Cypher isoforms and its homologue, ENH, in cardiac development and function and to gain insight into mechanisms by which mutations in Cypher causes cardiomyopathy.
Ablation of Cypher or ENH in mice results in cardiomyopathy. Many mutations in the human Cypher gene have been identified in patients with different forms of cardiomyopathy. Our proposed studies will help to understand the role of Cypher and its homologue, ENH, in cardiac development and function and to gain insight into mechanisms by which mutations in Cypher cause cardiomyopathy.
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