201. Loss of enigma homolog protein results in dilated cardiomyopathy.
- Author
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Cheng H, Kimura K, Peter AK, Cui L, Ouyang K, Shen T, Liu Y, Gu Y, Dalton ND, Evans SM, Knowlton KU, Peterson KL, and Chen J
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Alternative Splicing, Animals, Cardiomyopathy, Dilated physiopathology, Carrier Proteins genetics, Carrier Proteins physiology, Exons, Homeodomain Proteins genetics, Homeodomain Proteins physiology, LIM Domain Proteins, Mice, Mice, Knockout, Microfilament Proteins genetics, Muscle Proteins genetics, Myocardial Contraction genetics, Plasmids, Polymerase Chain Reaction, Protein Isoforms genetics, Systole genetics, Adaptor Proteins, Signal Transducing deficiency, Cardiomyopathy, Dilated genetics, Microfilament Proteins deficiency
- Abstract
Rationale: The Z-line, alternatively termed the Z-band or Z-disc, is a highly ordered structure at the border between 2 sarcomeres. Enigma subfamily proteins (Enigma, Enigma homolog protein, and Cypher) of the PDZ-LIM domain protein family are Z-line proteins. Among the Enigma subfamily, Cypher has been demonstrated to play a pivotal role in the structure and function of striated muscle, whereas the role of Enigma homolog protein (ENH) in muscle remains largely unknown., Objective: We studied the role of Enigma homolog protein in the heart using global and cardiac-specific ENH knockout mouse models., Methods and Results: We identified new exons and splice isoforms for ENH in the mouse heart. Impaired cardiac contraction and dilated cardiomyopathy were observed in ENH null mice. Mice with cardiac specific ENH deletion developed a similar dilated cardiomyopathy. Like Cypher, ENH interacted with Calsarcin-1, another Z-line protein. Moreover, biochemical studies showed that ENH, Cypher short isoform and Calsarcin-1 are within the same protein complex at the Z-line. Cypher short isoform and Calsarcin-1 proteins are specifically downregulated in ENH null hearts., Conclusions: We have identified an ENH-CypherS-Calsarcin protein complex at the Z-line. Ablation of ENH leads to destabilization of this protein complex and dilated cardiomyopathy.
- Published
- 2010
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