TitleNormalization of Naxos plakoglobin levels restores cardiac function in mice
AuthorsZhang, Zhiwei
Stroud, Matthew J.
Zhang, Jianlin
Fang, Xi
Ouyang, Kunfu
Kimura, Kensuke
Mu, Yongxin
Dalton, Nancy D.
Gu, Yusu
Bradford, William H.
Peterson, Kirk L.
Cheng, Hongqiang
Zhou, Xinmin
Chen, Ju
AffiliationUniv Calif San Diego, Sch Med, La Jolla, CA 92093 USA.
Cent S Univ, Xiangya Hosp 2, Dept Cardiothorac Surg, Changsha, Hunan, Peoples R China.
Peking Univ, Sch Chem Biol & Biotechnol, Shenzhen, Peoples R China.
Zhejiang Univ, Sch Med, Program Mol Cell Biol, Dept Pathol & Pathophysiol, Hangzhou 310003, Zhejiang, Peoples R China.
Univ Calif San Diego, Sch Med, 9500 Gilman Dr, La Jolla, CA 92093 USA.
KeywordsRIGHT-VENTRICULAR CARDIOMYOPATHY
EMBRYONIC HEART
DISEASE
DELETION
REVEALS
Issue Date2015
PublisherJOURNAL OF CLINICAL INVESTIGATION
CitationJOURNAL OF CLINICAL INVESTIGATION.2015,125,(4),1708-1712.
AbstractArrhythmogenic 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 plalcoglobin 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.
URIhttp://hdl.handle.net/20.500.11897/420634
ISSN0021-9738
DOI10.1172/JCI80335
IndexedSCI(E)
Appears in Collections:化学生物学与生物技术学院

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