Ju Chen Laboratory In the Department of Medicine

Understanding the role of Plakoglobin in Naxos disease

Arrhythmogenic cardiomyopathy (AC) is largely associated with mutations in intercalated disc proteins, and ultimately results in sudden cardiac death. A subset of patients with AC have Naxos disease, an autosomal recessive, cardiocutaneous disorder caused by a two base pair deletion in the JUP gene encoding the intercalated disc protein Plakoglobin. This mutation results in a truncated protein that is expressed at reduced levels. Specific ablation of Plakoglobin in mouse cardiomyocytes recapitulates many aspects of the phenotype observed in human AC patients. Conversely, others have shown that overexpression of the Naxos mutant truncated Plakoglobin also results in an AC-like phenotype. From the foregoing, it is currently unclear whether Naxos disease results from loss-of-function, or gain-of-function consequent to the Plakoglobin mutation.
Here, we have generated two knock-in mouse models in which the endogenous jup gene was engineered to express the mutant Naxos Plakoglobin. In one of these, the nonsense-mediated decay pathway was bypassed, resulting in normal levels of mutant Naxos Plakoglobin. Analyses of these mouse models revealed that restoration of Naxos mutant Plakoglobin to wildtype levels was sufficient to result in normal heart function. These data demonstrated that gain-of-function of the mutant protein does not underlie the clinical phenotype of Naxos patients, leaving the alternate explanation that insufficiency of Naxos protein accounts for disease manifestation. An important implication of our findings is that a viable therapeutic approach to Naxos disease will be to increase levels of truncated or wildtype Plakoglobin protein.
Read our new manuscript recently published in the Journal of Clinical Investigation

Image of cardiac tissue stained with DAPI (nuclei in blue),
cadherin and plakoglobin (in red and green).

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    Matt Stroud, PhD
    Lead postdoctoral scientist on the Naxos disease project.

    Zhiwei Zhang, PhD
    MD/PhD student on the Naxos disease project.

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