Normalization of Naxos plakoglobin levels restores cardiac function in mice

• Published in: The Journal of clinical investigation Vol. 125; no. 4; pp. 1708 - 1712
• Main Authors: Zhang, 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.04.2015
• Subjects: Animals; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - physiopathology; Arrhythmogenic Right Ventricular Dysplasia - genetics; Arrhythmogenic Right Ventricular Dysplasia - pathology; Biomedical research; Brief Report; Cardiomyocytes; Cardiomyopathy; Codon, Nonsense; Cytoskeletal proteins; Desmoplakins - genetics; Development and progression; Fibrosis; Frameshift Mutation; gamma Catenin - chemistry; gamma Catenin - deficiency; gamma Catenin - genetics; gamma Catenin - physiology; Gene Knock-In Techniques; Genes; Genes, Lethal; Genetic aspects; Genotype & phenotype; Hair Diseases - genetics; Hair Diseases - pathology; Health aspects; Heart; Heart diseases; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Humans; Keratoderma, Palmoplantar - genetics; Keratoderma, Palmoplantar - pathology; Laboratory animals; Mice; Microscopy; Mutation; Myocardial Contraction; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nonsense Mediated mRNA Decay; Peptide Fragments - physiology; Phenotype; Proteins; RNA Stability; RNA, Messenger - metabolism; Rodents; Sequence Deletion; Studies; Wnt Signaling Pathway
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci80335

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.