title: Normalization of Naxos plakoglobin levels restores cardiac function in mice.
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.forename: Zhiwei
authors.initials: Z
authors.lastname: Zhang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Stroud
authors.forename: Jianlin
authors.initials: J
authors.lastname: Zhang
authors.forename: Xi
authors.initials: X
authors.lastname: Fang
authors.forename: Kunfu
authors.initials: K
authors.lastname: Ouyang
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kimura
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Mu
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.forename: William H
authors.initials: WH
authors.lastname: Bradford
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Cheng
authors.forename: Xinmin
authors.initials: X
authors.lastname: Zhou
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000473:pathology; D018389:Codon, Nonsense; D051180:Desmoplakins / Q000235:genetics*; D005355:Fibrosis; D016368:Frameshift Mutation; D055879:Gene Knock-In Techniques; D005804:Genes, Lethal; D006201:Hair Diseases / Q000235:genetics* / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D059365:Nonsense Mediated mRNA Decay; D010446:Peptide Fragments / Q000502:physiology; D010641:Phenotype; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D017384:Sequence Deletion; D060449:Wnt Signaling Pathway; D051185:gamma Catenin / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018389:Codon, Nonsense; D051180:Desmoplakins; C495292:JUP protein, human; C495293:Jup protein, mouse; D010446:Peptide Fragments; D012333:RNA, Messenger; D051185:gamma Catenin