title: Characterizing the Molecular Pathology of Arrhythmogenic Cardiomyopathy in Patient Buccal Mucosa Cells.
abstract: BACKGROUND
  Analysis of myocardium has revealed mechanistic insights into arrhythmogenic cardiomyopathy but cardiac samples are difficult to obtain from probands and especially from family members. To identify a potential surrogate tissue, we characterized buccal mucosa cells.
  
  
  RESULTS
  Buccal cells from patients, mutation carriers, and controls were immunostained and analyzed in a blinded fashion. In additional studies, buccal cells were grown in vitro and incubated with SB216763. Immunoreactive signals for the desmosomal protein plakoglobin and the major cardiac gap junction protein Cx43 were markedly diminished in buccal mucosa cells from arrhythmogenic cardiomyopathy patients with known desmosomal mutations when compared with controls. Plakoglobin and Cx43 signals were also reduced in most family members who carried disease alleles but showed no evidence of heart disease. Signal for the desmosomal protein plakophilin-1 was reduced in buccal mucosa cells in patients with PKP2 mutations but not in those with mutations in other desmosomal genes. Signal for the desmosomal protein desmoplakin was reduced in buccal mucosa cells from patients with mutations in DSP, DSG2, or DSC2 but not in PKP2 or JUP. Abnormal protein distributions were reversed in cultured cells incubated with SB216763, a small molecule that rescues the disease phenotype in cardiac myocytes.
  
  
  CONCLUSIONS
  Buccal mucosa cells from arrhythmogenic cardiomyopathy patients exhibit changes in the distribution of cell junction proteins similar to those seen in the heart. These cells may prove useful in future studies of disease mechanisms and drug screens for effective therapies in arrhythmogenic cardiomyopathy.
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).
authors: Angeliki
authors: A
authors: Asimaki
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).
authors: Alexandros
authors: A
authors: Protonotarios
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).
authors: Cynthia A
authors: CA
authors: James
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).
authors: Stephen P
authors: SP
authors: Chelko
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).
authors: Crystal
authors: C
authors: Tichnell
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).
authors: Brittney
authors: B
authors: Murray
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).
authors: Adalena
authors: A
authors: Tsatsopoulou
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).
authors: Aris
authors: A
authors: Anastasakis
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).
authors: Anneline
authors: A
authors: te Riele
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).
authors: André G
authors: AG
authors: Kléber
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).
authors: Daniel P
authors: DP
authors: Judge
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).
authors: Hugh
authors: H
authors: Calkins
authors: From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis). jsaffitz@bidmc.harvard.edu.
authors: Jeffrey E
authors: JE
authors: Saffitz
mesh_terms: D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D015142:Baltimore; D001900:Boston; D016022:Case-Control Studies; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D004252:DNA Mutational Analysis; D051187:Desmocollins / Q000235:genetics; D051301:Desmoglein 2 / Q000235:genetics; D051180:Desmoplakins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006115:Greece; D006801:Humans; D007150:Immunohistochemistry; D009061:Mouth Mucosa / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D051191:Plakophilins / Q000235:genetics / Q000378:metabolism; D051185:gamma Catenin
chemical_list: D018031:Connexin 43; C081561:DSC2 protein, human; C495314:DSG2 protein, human; C495294:DSP protein, human; D051187:Desmocollins; D051301:Desmoglein 2; D051180:Desmoplakins; C500216:GJA1 protein, human; C495292:JUP protein, human; C495337:PKP2 protein, human; D051191:Plakophilins; D051185:gamma Catenin
keywords: arrhythmogenic right ventricular cardiomyopathy; buccal mucosa cells; connexin43; desmosome cardiomyopathy; diagnosis; plakoglobin