Loss of enigma homolog protein results in dilated cardiomyopathy.
BACKGROUND
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.


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.
Department of Medicine, University of California San Diego, La Jolla, 92093, USA.
Hongqiang
H
Cheng
Kensuke
K
Kimura
Angela K
AK
Peter
Li
L
Cui
Kunfu
K
Ouyang
Tao
T
Shen
Yujie
Y
Liu
Yusu
Y
Gu
Nancy D
ND
Dalton
Sylvia M
SM
Evans
Kirk U
KU
Knowlton
Kirk L
KL
Peterson
Ju
J
Chen
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics; D017398:Alternative Splicing; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D005091:Exons; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency* / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009200:Myocardial Contraction / Q000235:genetics; D010957:Plasmids; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000235:genetics; D013599:Systole / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C510085:ENH protein, mouse; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C485639:Ldb3 protein, mouse; D008840:Microfilament Proteins; D009124:Muscle Proteins; C523647:Myoz1 protein, mouse; D020033:Protein Isoforms