TitleCardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death
AuthorsZheng, Ming
Cheng, Hongqiang
Li, Xiaodong
Zhang, Jianlin
Cui, Li
Ouyang, Kunfu
Han, Liang
Zhao, Ting
Gu, Yusu
Dalton, Nancy D.
Bang, Marie-Louise
Peterson, Kirk L.
Chen, Ju
AffiliationUniv Calif San Diego, Dept Med, La Jolla, CA 92093 USA.
Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China.
CNR, ITB, Dulbecco Telethon Inst, I-20090 Milan, Italy.
IRCCS Multimedia Sci & Technol Pole, I-20138 Milan, Italy.
Univ Calif San Diego, Dept Med, 9500 Gilman Dr, La Jolla, CA 92093 USA.
KeywordsDYSTROPHIN-GLYCOPROTEIN COMPLEX
GIRDLE MUSCULAR-DYSTROPHY
ACTIVATED PROTEIN-KINASE
HEAVY-CHAIN GENE
Z-DISC PROTEINS
HEART-FAILURE
HYPERTROPHIC CARDIOMYOPATHY
SARCOMERIC PROTEIN
TROPONIN-T
MUTATIONS
Issue Date2009
Publisherhuman molecular genetics
CitationHUMAN MOLECULAR GENETICS.2009,18,(4),701-713.
AbstractAccumulating 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.
URIhttp://hdl.handle.net/20.500.11897/396685
ISSN0964-6906
DOI10.1093/hmg/ddn400
IndexedSCI(E)
Appears in Collections:分子医学研究所

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