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Review
. 2007 Nov;17(8):258-62.
doi: 10.1016/j.tcm.2007.09.002.

"Z"eroing in on the role of Cypher in striated muscle function, signaling, and human disease

Farah Sheikh  1 , Marie-Louise Bang, Stephan Lange, Ju Chen
Affiliations
Review

"Z"eroing in on the role of Cypher in striated muscle function, signaling, and human disease

Farah Sheikh et al. Trends Cardiovasc Med. 2007 Nov.

Abstract

The striated muscle Z line, a multiprotein complex at the boundary between sarcomeres, plays an integral role in maintaining striated muscle structure and function. Multiple Z-line-associated proteins have been identified and shown to play an increasingly important role in the pathogenesis of human muscle disease. Cypher/Z-band alternatively spliced PDZ-motif protein, a PDZ-LIM protein in the Z line, binds to alpha-actinin (via its PDZ domain) and has been suggested to function as a linker-strut to maintain cytoskeletal structural integrity during contraction. Cypher may also participate in signaling pathways by binding to protein kinase C via its LIM domains. Analysis of Cypher-deficient mice has revealed that Cypher plays an integral role in Z-line maintenance/integrity of striated muscles and the pathogenesis of congenital myopathies, including cardiomyopathy. These studies have led to the subsequent discovery of Cypher mutations in human patients with dilated cardiomyopathy, hypertrophic cardiomyopathy, as well as skeletal muscle myopathies, which have been recently termed zaspopathies. The recent discovery of various alternatively spliced isoforms of Cypher with potentially distinct structural and signaling roles brings a different level of complexity to the mechanisms underlying Cypher-based human myopathies. This review will focus on recent developments on the role of Cypher and its isoforms in striated muscle structure, signaling, and disease to provide insights into the mechanisms involved in the pathogenesis of Z-line-associated human myopathies.

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Figures

Figure 1
Figure 1
Model of the sarcomeric Z-line and costamere highlighting Cypher in the context of other Z-line associated proteins.
Figure 2
Figure 2
The genetic organization of the human Cypher/ZASP gene with the identified mutations shown in different colors to illustrate diseases associated with each mutation. The PDZ domain, ZM motifs, and LIM domains are highlighted. Transcriptional start (ATG) and stop (TAG and TAA) codons are also delineated. INLVM: isolated non-compaction of the left ventricular myocardium; DCM: dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy. Exon 9 is the last exon of short Cypher isoforms, while exon 16 is the last exon of large Cypher isoforms.
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