{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPlakophilin‐2 (PKP2) is a critical structural protein of the desmosome that ensures robust cell–cell adhesion in the heart and other tissues. In cardiomyocytes PKP2 localizes to the intercalated disc where it scaffolds key desmosomal components – including desmoplakin, plakoglobin, desmogleins and desmocollins – to establish and maintain mechanical integrity. Consistent with this structural role, multiple clinical studies have identified heterozygous PKP2 mutations as the most frequent genetic cause of arrhythmogenic right ventricular cardiomyopathy (ARVC), a disorder characterized by progressive fibrofatty replacement of myocytes, conduction abnormalities and ventricular arrhythmias with variable penetrance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role as an adhesive scaffold, PKP2 is increasingly recognized as a regulator of intracellular signaling pathways that govern both electrical and mechanical properties. Experimental models have demonstrated that diminished PKP2 expression not only disrupts desmosome assembly but also reduces sodium current, thereby perturbing electrical propagation. The PKP2 head domain mediates interactions with a broad repertoire of proteins including beta‐catenin, thereby modulating T cell factor signaling, while engaging protein kinase C– and RhoA–dependent cascades that control actin reorganization and focal adhesion dynamics. Such interactions underscore the role of PKP2 in integrating junctional assembly with intracellular pathways that are essential for maintaining proper cardiomyocyte function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPKP2 also exhibits versatile functions outside its classical role in cardiac desmosomes. In non‐cardiac contexts, for example, elevated PKP2 has been shown to act as a positive regulator of epidermal growth factor receptor (EGFR) signaling, enhancing receptor dimerization and phosphorylation to promote cancer cell proliferation and migration. Moreover, recent interactome studies have identified PKP2 as a natural inhibitor of influenza A virus replication, where it competes with viral proteins to disrupt the viral polymerase complex. Altered PKP2 expression in transformed mesenchymal and stromal cells further impacts actin cytoskeletal reorganization, integrin expression and Wnt/β–catenin feedback loops, thereby influencing cell adhesion, motility and tissue remodeling in diverse disease settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "50"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Brenda Gerull, Arnd Heuser, Thomas Wichter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1461"}], "href": "https://doi.org/10.1038/ng1461"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15489853"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15489853"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "J Peter van Tintelen, Mark M Entius, Zahurul A Bhuiyan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.105.609719"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.105.609719"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16567567"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16567567"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Suet Nee Chen, Priyatansh Gurha, Raffaella Lombardi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The hippo pathway is activated and is a causal mechanism for adipogenesis in arrhythmogenic cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.114.302810"}], "href": "https://doi.org/10.1161/CIRCRESAHA.114.302810"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24276085"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24276085"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Darshan Dalal, Lorraine H Molin, Jonathan Piccini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.105.568642"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.105.568642"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16549640"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16549640"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "A Dénise den Haan, Boon Yew Tan, Michelle N Zikusoka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Cardiovasc Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCGENETICS.109.858217"}], "href": "https://doi.org/10.1161/CIRCGENETICS.109.858217"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20031617"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20031617"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Petros Syrris, Deirdre Ward, Angeliki Asimaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.105.561654"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.105.561654"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16415378"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16415378"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Darshan Dalal, Cynthia James, Rajiv Devanagondi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Am Coll Cardiol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jacc.2006.06.045"}], "href": "https://doi.org/10.1016/j.jacc.2006.06.045"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17010805"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17010805"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Mark M Awad, Darshan Dalal, Crystal Tichnell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.9461"}], "href": "https://doi.org/10.1002/humu.9461"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17041889"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17041889"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "David A Watkins, Neil Hendricks, Gasnat Shaboodien, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical features, survival experience, and profile of plakophylin-2 gene mutations in participants of the arrhythmogenic right ventricular cardiomyopathy registry of South Africa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Heart Rhythm (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.hrthm.2009.08.018"}], "href": "https://doi.org/10.1016/j.hrthm.2009.08.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19880068"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19880068"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Prince J Kannankeril, Zahurul A Bhuiyan, Dawood Darbar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Arrhythmogenic right ventricular cardiomyopathy due to a novel plakophilin 2 mutation: wide spectrum of disease in mutation carriers within a family."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Heart Rhythm (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.hrthm.2006.04.028"}], "href": "https://doi.org/10.1016/j.hrthm.2006.04.028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16876743"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16876743"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Ilena Egle Astrid Li Mura, Barbara Bauce, Andrea Nava, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2013.39"}], "href": "https://doi.org/10.1038/ejhg.2013.39"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23486541"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23486541"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Xiaoliang Qiu, Wenling Liu, Dayi Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations of plakophilin-2 in Chinese with arrhythmogenic right ventricular dysplasia/cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Cardiol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.amjcard.2009.01.356"}], "href": "https://doi.org/10.1016/j.amjcard.2009.01.356"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19427443"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19427443"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Marta Pérez-Hernández, Chantal J M van Opbergen, Navratan Bagwan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of Nuclear Envelope Integrity and Increased Oxidant Production Cause DNA Damage in Adult Hearts Deficient in PKP2: A Molecular Substrate of ARVC."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.122.060454"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.122.060454"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35959657"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35959657"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Mireia Alcalde, Oscar Campuzano, Paola Berne, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0100560"}], "href": "https://doi.org/10.1371/journal.pone.0100560"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24967631"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24967631"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Marina Cerrone, Xianming Lin, Mingliang Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.113.003077"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.113.003077"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24352520"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24352520"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Xinyu Chen, Stefan Bonne, Mechthild Hatzfeld, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protein binding and functional characterization of plakophilin 2. Evidence for its diverse roles in desmosomes and beta -catenin signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M108765200"}], "href": "https://doi.org/10.1074/jbc.M108765200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11790773"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11790773"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Amanda E Bass-Zubek, Ryan P Hobbs, Evangeline V Amargo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plakophilin 2: a critical scaffold for PKC alpha that regulates intercellular junction assembly."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200712133"}], "href": "https://doi.org/10.1083/jcb.200712133"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18474624"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18474624"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Lisa M Godsel, Adi D Dubash, Amanda E Bass-Zubek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plakophilin 2 couples actomyosin remodeling to desmosomal plaque assembly via RhoA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.E10-02-0131"}], "href": "https://doi.org/10.1091/mbc.E10-02-0131"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20554761"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20554761"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Zahurul A Bhuiyan, Jan D H Jongbloed, Jasper van der Smagt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Desmoglein-2 and desmocollin-2 mutations in dutch arrhythmogenic right ventricular dysplasia/cardiomypathy patients: results from a multicenter study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Cardiovasc Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCGENETICS.108.839829"}], "href": "https://doi.org/10.1161/CIRCGENETICS.108.839829"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20031616"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20031616"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Lee M Fidler, Gregory J Wilson, Fanfan Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Abnormal connexin43 in arrhythmogenic right ventricular cardiomyopathy caused by plakophilin-2 mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1582-4934.2008.00438.x"}], "href": "https://doi.org/10.1111/j.1582-4934.2008.00438.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18662195"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18662195"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Rosy Joshi-Mukherjee, Wanda Coombs, Hassan Musa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of the molecular phenotype of two arrhythmogenic right ventricular cardiomyopathy (ARVC)-related plakophilin-2 (PKP2) mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Heart Rhythm (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.hrthm.2008.09.009"}], "href": "https://doi.org/10.1016/j.hrthm.2008.09.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19084810"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19084810"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Florian Kirchner, Anja Schuetz, Leif-Hendrik Boldt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular insights into arrhythmogenic right ventricular cardiomyopathy caused by plakophilin-2 missense mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Cardiovasc Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCGENETICS.111.961854"}], "href": "https://doi.org/10.1161/CIRCGENETICS.111.961854"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22781308"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22781308"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Mingchang Zhang, Fabio Tavora, Joao Bosco Oliveira, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PKP2 mutations in sudden death from arrhythmogenic right ventricular cardiomyopathy (ARVC) and sudden unexpected death with negative autopsy (SUDNA)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ J (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1253/circj.cj-11-0747"}], "href": "https://doi.org/10.1253/circj.cj-11-0747"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22019812"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22019812"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Jennifer L Koetsier, Evangeline V Amargo, Viktor Todorović, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plakophilin 2 affects cell migration by modulating focal adhesion dynamics and integrin protein expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jid.2013.266"}], "href": "https://doi.org/10.1038/jid.2013.266"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23884246"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23884246"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "F Ramond, A Janin, S Di Filippo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Homozygous PKP2 deletion associated with neonatal left ventricle noncompaction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cge.12780"}], "href": "https://doi.org/10.1111/cge.12780"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27030002"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27030002"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Hiroyuki Inoue, Satoki Nakamura, Shuichiro Higo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modeling reduced contractility and impaired desmosome assembly due to plakophilin-2 deficiency using isogenic iPS cell-derived cardiomyocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cell Reports (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stemcr.2021.12.016"}], "href": "https://doi.org/10.1016/j.stemcr.2021.12.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35063130"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35063130"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Veronique Fressart, Guillaume Duthoit, Erwan Donal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Europace (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/europace/euq104"}], "href": "https://doi.org/10.1093/europace/euq104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20400443"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20400443"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Francisco M Cruz, David Sanz-Rosa, Marta Roche-Molina, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exercise triggers ARVC phenotype in mice expressing a disease-causing mutated version of human plakophilin-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Am Coll Cardiol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jacc.2015.01.045"}], "href": "https://doi.org/10.1016/j.jacc.2015.01.045"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25857910"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25857910"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "A H Christensen, M Benn, H Bundgaard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2010.077891"}], "href": "https://doi.org/10.1136/jmg.2010.077891"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20864495"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20864495"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Abhishek C Sawant, Anneline S J M Te Riele, Crystal Tichnell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Safety of American Heart Association-recommended minimum exercise for desmosomal mutation carriers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Heart Rhythm (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.hrthm.2015.08.035"}], "href": "https://doi.org/10.1016/j.hrthm.2015.08.035"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26321091"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26321091"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Lingyan Wang, Bishi Fu, Wenjun Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Comparative influenza protein interactomes identify the role of plakophilin 2 in virus restriction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms13876"}], "href": "https://doi.org/10.1038/ncomms13876"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28169297"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28169297"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Moniek G P J Cox, Jasper J van der Smagt, Maartje Noorman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Arrhythmogenic right ventricular dysplasia/cardiomyopathy diagnostic task force criteria: impact of new task force criteria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Arrhythm Electrophysiol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCEP.109.927202"}], "href": "https://doi.org/10.1161/CIRCEP.109.927202"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20215590"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20215590"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Alexis Hermida, Véronique Fressart, Francoise Hidden-Lucet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High risk of heart failure associated with desmoglein-2 mutations compared to plakophilin-2 mutations in arrhythmogenic right ventricular cardiomyopathy/dysplasia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Heart Fail (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ejhf.1423"}], "href": "https://doi.org/10.1002/ejhf.1423"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30790397"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30790397"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Torsten B Rasmussen, Peter H Nissen, Johan Palmfeldt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Cardiovasc Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCGENETICS.113.000338"}], "href": "https://doi.org/10.1161/CIRCGENETICS.113.000338"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24704780"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24704780"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Alex Hørby Christensen, Marianne Benn, Anne Tybjaerg-Hansen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiology (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000263456"}], "href": "https://doi.org/10.1159/000263456"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19955750"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19955750"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Kei-ichiro Arimoto, Christoph Burkart, Ming Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plakophilin-2 promotes tumor development by enhancing ligand-dependent and -independent epidermal growth factor receptor dimerization and activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00758-14"}], "href": "https://doi.org/10.1128/MCB.00758-14"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25113560"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25113560"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Annukka M Lahtinen, Annukka Lehtonen, Maija Kaartinen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plakophilin-2 missense mutations in arrhythmogenic right ventricular cardiomyopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cardiol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ijcard.2007.03.137"}], "href": "https://doi.org/10.1016/j.ijcard.2007.03.137"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17521752"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17521752"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "C Barahona-Dussault, B Benito, O Campuzano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1399-0004.2009.01282.x"}], "href": "https://doi.org/10.1111/j.1399-0004.2009.01282.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19863551"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19863551"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "David J Tester, Jaeger P Ackerman, John R Giudicessi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plakophilin-2 Truncation Variants in Patients Clinically Diagnosed With Catecholaminergic Polymorphic Ventricular Tachycardia and Decedents With Exercise-Associated Autopsy Negative Sudden Unexplained Death in the Young."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JACC Clin Electrophysiol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jacep.2018.09.010"}], "href": "https://doi.org/10.1016/j.jacep.2018.09.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30678776"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30678776"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Baerbel Klauke, Anna Gaertner-Rommel, Uwe Schulz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0189489"}], "href": "https://doi.org/10.1371/journal.pone.0189489"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29253866"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29253866"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Hisaya Takahashi, Hiroyoshi Nakatsuji, Masayuki Takahashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Up-regulation of plakophilin-2 and Down-regulation of plakophilin-3 are correlated with invasiveness in bladder cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Urology (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.urology.2011.08.049"}], "href": "https://doi.org/10.1016/j.urology.2011.08.049"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22119253"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22119253"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "S Bonné, J van Hengel, F van Roy "}, {"type": "b", "children": [{"type": "t", "text": "Chromosomal mapping of human armadillo genes belonging to the p120(ctn)/plakophilin subfamily."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genomics (1998)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1006/geno.1998.5398"}], "href": "https://doi.org/10.1006/geno.1998.5398"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "9721216"}], "href": "https://pubmed.ncbi.nlm.nih.gov/9721216"}]}, {"type": "r", "ref": 43, "children": [{"type": "t", "text": "Guzin Gonullu Demirag, Yurdanur Sullu, Idris Yucel "}, {"type": "b", "children": [{"type": "t", "text": "Expression of Plakophilins (PKP1, PKP2, and PKP3) in breast cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Oncol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12032-011-0071-1"}], "href": "https://doi.org/10.1007/s12032-011-0071-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21947748"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21947748"}]}, {"type": "r", "ref": 44, "children": [{"type": "t", "text": "Judith A Groeneweg, Paul A van der Zwaag, Jan D H Jongbloed, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Left-dominant arrhythmogenic cardiomyopathy in a large family: associated desmosomal or nondesmosomal genotype?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Heart Rhythm (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.hrthm.2012.12.020"}], "href": "https://doi.org/10.1016/j.hrthm.2012.12.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23270881"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23270881"}]}, {"type": "r", "ref": 45, "children": [{"type": "t", "text": "Chih-Chieh Yu, Cheng-Han Yu, Chia-Hsiang Hsueh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Arrhythmogenic right ventricular dysplasia: clinical characteristics and identification of novel desmosome gene mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Formos Med Assoc (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0929-6646(08)60168-0"}], "href": "https://doi.org/10.1016/S0929-6646(08"}, {"type": "t", "text": "60168-0) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18632414"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18632414"}]}, {"type": "r", "ref": 46, "children": [{"type": "t", "text": "Steffen Rickelt, Stefanie Winter-Simanowski, Edeltraut Noffz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of plakophilin-2 and its acquisition to adherens junctions identifies a novel molecular ensemble of cell-cell-attachment characteristic for transformed mesenchymal cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.24552"}], "href": "https://doi.org/10.1002/ijc.24552"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19551809"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19551809"}]}, {"type": "r", "ref": 47, "children": [{"type": "t", "text": "Núria Niell, María Jesús Larriba, Gemma Ferrer-Mayorga, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human PKP2/plakophilin-2 gene is induced by Wnt/β-catenin in normal and colon cancer-associated fibroblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.31104"}], "href": "https://doi.org/10.1002/ijc.31104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29044515"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29044515"}]}, {"type": "r", "ref": 48, "children": [{"type": "t", "text": "Chad Hall, Shumin Li, Hong Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Arrhythmogenic right ventricular cardiomyopathy plakophilin-2 mutations disrupt desmosome assembly and stability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Commun Adhes (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15419060903009329"}], "href": "https://doi.org/10.1080/15419060903009329"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19533476"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19533476"}]}, {"type": "r", "ref": 49, "children": [{"type": "t", "text": "Xiang-Lin Hao, Zhen Tian, Fei Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plakophilin-2 accelerates cell proliferation and migration through activating EGFR signaling in lung adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pathol Res Pract (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.prp.2019.152438"}], "href": "https://doi.org/10.1016/j.prp.2019.152438"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31126818"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31126818"}]}, {"type": "r", "ref": 50, "children": [{"type": "t", "text": "Steffen Rickelt, Stefania Rizzo, Yvette Doerflinger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel kind of tumor type-characteristic junction: plakophilin-2 as a major protein of adherens junctions in cardiac myxomata."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mod Pathol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/modpathol.2010.138"}], "href": "https://doi.org/10.1038/modpathol.2010.138"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20693980"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20693980"}]}]}]}