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Normalization of Naxos plakoglobin levels restores cardiac function in mice
Zhiwei Zhang, … , Xinmin Zhou, Ju Chen
Zhiwei Zhang, … , Xinmin Zhou, Ju Chen
Published February 23, 2015
Citation Information: J Clin Invest. 2015;125(4):1708-1712. https://doi.org/10.1172/JCI80335.
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Brief Report Cardiology

Normalization of Naxos plakoglobin levels restores cardiac function in mice

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Abstract

Arrhythmogenic cardiomyopathy (AC) is associated with mutations in genes encoding intercalated disc proteins and ultimately results in sudden cardiac death. A subset of patients with AC have the autosomal recessive cardiocutaneous disorder Naxos disease, which is caused by a 2–base pair deletion in the plakoglobin-encoding gene JUP that results in a truncated protein with reduced expression. In mice, cardiomyocyte-specific plakoglobin deficiency recapitulates many aspects of human AC, and overexpression of the truncated Naxos-associated plakoglobin also results in an AC-like phenotype; therefore, it is unclear whether Naxos disease results from loss or gain of function consequent to the plakoglobin mutation. Here, we generated 2 knockin mouse models in which endogenous Jup was engineered to express the Naxos-associated form of plakoglobin. In one model, Naxos plakoglobin bypassed the nonsense-mediated mRNA decay pathway, resulting in normal levels of the truncated plakoglobin. Moreover, restoration of Naxos plakoglobin to WT levels resulted in normal heart function. Together, these data indicate that a gain of function in the truncated form of the protein does not underlie the clinical phenotype of patients with Naxos disease and instead suggest that insufficiency of the truncated Naxos plakoglobin accounts for disease manifestation. Moreover, these results suggest that increasing levels of truncated or WT plakoglobin has potential as a therapeutic approach to Naxos disease.

Authors

Zhiwei Zhang, Matthew J. Stroud, Jianlin Zhang, Xi Fang, Kunfu Ouyang, Kensuke Kimura, Yongxin Mu, Nancy D. Dalton, Yusu Gu, William H. Bradford, Kirk L. Peterson, Hongqiang Cheng, Xinmin Zhou, Ju Chen

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Figure 3

ICD protein expression levels and localizations were unaffected in FuseNax mice.

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ICD protein expression levels and localizations were unaffected in FuseN...
(A and B) Immunofluorescence of β-catenin and connexin 43 (Cx43), respectively, in mouse myocardium. Note similar localization and levels of both β-catenin (white arrowheads) and Cx43 (white arrows) at ICDs between WT and FuseNax (MU) mice. n = 3 mice per genotype. (C–E) Western blots of the indicated ICD proteins. Arrowheads show the predicted MW, and the arrow shows the predicted MW of mutant plakoglobin (PKG). Note that most protein levels are unaffected in the FuseNax mouse hearts. Cx43, connexin 43; GJ, gap junction. n = 6 mice per genotype. (F) Subcellular fractionation experiments with WT and FuseNax mouse hearts. Note that plakoglobin in both WT and FuseNax (asterisk) is in cytoskeletal (SKEL) fractions in heart tissue. As controls for fractionation, GAPDH is in the cytoplasm (CYT), histone 3 is in the nuclear fraction (NUC), and vinculin is predominantly in the cytoskeletal fraction. MEM, membrane fraction. n = 6 mice per genotype. (G) Immunofluorescence of mouse myocardium using antibodies generated against plakoglobin. Note localization of plakoglobin (green) to ICD (white arrows) and colocalization with N-cadherin. n = 3 mice per genotype. (H) qRT-PCR analysis of the indicated genes, showing the fold change relative to 18S from 10-month-old mice. Note that expression of genes downstream of the Wnt/β-catenin pathway was unaffected (c-myc, cyclin D1) as was the profibrotic marker TGF-β (Tgfb1) and the adipogenic gene, adiponectin. n = 8 mice per genotype. Data represent mean ± SEM. Two-tailed Student’s t test was performed on data. Scale bar: 10 μm.

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