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Desmosome mutation

Jennifer Karmouch, Alexandros Protonotarios, Petros Syrris
PURPOSE OF REVIEW: To date 16 genes have been associated with arrhythmogenic cardiomyopathy (ACM). Mutations in these genes can lead to a broad spectrum of phenotypic expression ranging from disease affecting predominantly the right or left ventricle, to biventricular subtypes. Understanding the genetic causes of ACM is important in diagnosis and management of the disorder. This review summarizes recent advances in molecular genetics and discusses the application of next-generation sequencing technology in genetic testing in ACM...
March 14, 2018: Current Opinion in Cardiology
Alice Giuliodori, Giorgia Beffagna, Giulia Marchetto, Chiara Fornetto, Francesco Vanzi, Stefano Toppo, Nicola Facchinello, Mattia Santimaria, Andrea Vettori, Stefania Rizzo, Mila Della Barbera, Kalliopi Pilichou, Francesco Argenton, Gaetano Thiene, Natascia Tiso, Cristina Basso
Aims: Arrhythmogenic cardiomyopathy (AC) is an inherited heart disease characterized by life-threatening ventricular arrhythmias and fibro-fatty replacement of the myocardium. More than 60% of AC patients show pathogenic mutations in genes encoding for desmosomal proteins. By focusing our attention on the AC8 form, linked to the junctional protein Desmoplakin (DSP), we present here a zebrafish model of DSP deficiency, exploited to identify early changes of cell signalling in the cardiac region...
March 7, 2018: Cardiovascular Research
Li Wang, Shenghua Liu, Hongliang Zhang, Shengshou Hu, Yingjie Wei
Arrhythmogenic cardiomyopathy (AC) is an inherited disorder that is predominantly present in the right ventricular myocardium. Mutations in the genes encoding the desmosomal protein are thought to underlie the pathogenesis of AC. Since AC is genetically heterogeneous and phenotypically diverse, modifier genes and environmental factors have an important role in disease expression. The aim of the present study was to identify AC-associated desmosomal gene variations, and examine the expression levels of intercalated disc proteins in AC patients who carry the variations (DSG2 p...
March 2018: Experimental and Therapeutic Medicine
Zinaida Dedeić, Gopinath Sutendra, Ying Hu, Kathryn Chung, Elizabeth A Slee, Michael J White, Felix Y Zhou, Robert D Goldin, David J P Ferguson, Debra McAndrew, Jurgen E Schneider, Xin Lu
Desmosome components are frequently mutated in cardiac and cutaneous disorders in animals and humans and enhanced inflammation is a common feature of these diseases. Previous studies showed that inhibitor of Apoptosis Stimulating p53 Protein (iASPP) regulates desmosome integrity at cell-cell junctions and transcription in the nucleus, and its deficiency causes cardiocutaneous disorder in mice, cattle, and humans. As iASPP is a ubiquitously expressed shuttling protein with multiple functions, a key question is whether the observed cardiocutaneous phenotypes are caused by loss of a cell autonomous role of iASPP in cardiomyocytes and keratinocytes specifically or by a loss of iASPP in other cell types such as immune cells...
January 19, 2018: Cell Death and Differentiation
Flor Evangelista, Aleeza J Roth, Phillip Prisayanh, Brenda R Temple, Ning Li, Ye Qian, Donna A Culton, Zhi Liu, Oliver J Harrison, Julia Brasch, Barry Honig, Lawrence Shapiro, Luis A Diaz
Fogo Selvagem (FS), the endemic form of pemphigus foliaceus, is mediated by pathogenic IgG4 autoantibodies against the amino-terminal extracellular cadherin domain of the desmosomal cadherin desmoglein 1 (Dsg1). Here we define the detailed epitopes of these pathogenic antibodies. Proteolytic footprinting showed that IgG4 from 95% of FS donor sera (19/20) recognized a 16-residue peptide (A129LNSMGQDLERPLELR144) from the EC1 domain of Dsg1 that overlaps the binding site for an adhesive-partner desmosomal cadherin molecule...
January 4, 2018: Journal of Autoimmunity
Luca Puzzi, Daniele Borin, Valentina Martinelli, Luisa Mestroni, David P Kelsell, Orfeo Sbaizero
In a tissue continuously challenged by mechanical stresses, such as the skin or the heart, cells perceive information about their microenvironment through several adhesive protein complexes and activate cell-signaling events to maintain tissue cohesion. Consequently, alteration of cell adhesion components leads to aberrant assembly of the associated cytoplasmic scaffolding and signaling pathways, which may reflect changes to the tissue physiology and mechanical resistance. Desmoplakin is an essential component of the cell-cell junction, anchoring the desmosomal protein complex to the intermediate filaments (IFs)...
December 19, 2017: Micron: the International Research and Review Journal for Microscopy
Stefan Kippenberger, Johannes Kleemann, Markus Meissner, Katja Steinhorst, Jutta Müller, Christos C Zouboulis, Roland Kaufmann, Nadja Zöller
BACKGROUND: Mechanical stress is an ubiquitous challenge of human cells with fundamental impact on cell physiology. Previous studies have shown that stretching promotes signalling cascades involved in proliferation and tissue enlargement. OBJECTIVE: The present study is dedicated to learn more about cellular structures contributing to perception and signal transmission of cell stretch. In particular, we hypothesized that desmosmal contacts and the adjacent keratin filament build an intercellular matrix providing information about the mechanical load...
March 2018: Journal of Dermatological Science
Yuko Wada, Seiko Ohno, Takeshi Aiba, Minoru Horie
BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy mainly caused by desmosomal gene mutation. More than half of Caucasian probands have desmosomal mutations, which lead to earlier onset of ventricular arrhythmias. Among non-Caucasians, the genetic background of ARVD/C probands and its prognostic impact remain unclear. METHODS AND RESULTS: We genotyped 99 unrelated Japanese ARVD/C probands for plakophilin 2 (PKP2), desmoglein 2 (DSG2), desmoplakin (DSP), and desmocollin 2 (DSC2) between 2005 and 2014...
November 2017: Molecular Genetics & Genomic Medicine
Mareike Dieding, Jana Davina Debus, Raimund Kerkhoff, Anna Gaertner-Rommel, Volker Walhorn, Hendrik Milting, Dario Anselmetti
Cadherins are calcium dependent adhesion proteins that establish the intercellular mechanical contact by bridging the gap to adjacent cells. Desmoglein-2 (Dsg2) is a specific cadherin of the cell-cell contact in cardiac desmosomes. Mutations in the DSG2-gene are regarded to cause arrhythmogenic (right ventricular) cardiomyopathy (ARVC) which is a rare but severe heart muscle disease. The molecular pathomechanisms of the vast majority of DSG2 mutations, however, are unknown. Here, we investigated the homophilic binding of wildtype Dsg2 and two mutations which are associated with ARVC...
October 23, 2017: Scientific Reports
Kalliopi Pilichou, Elisabetta Lazzarini, Ilaria Rigato, Rudy Celeghin, Marzia De Bortoli, Marina Perazzolo Marra, Marco Cason, Jan Jongbloed, Martina Calore, Stefania Rizzo, Daniela Regazzo, Giulia Poloni, Sabino Iliceto, Luciano Daliento, Pietro Delise, Domenico Corrado, J Peter Van Tintelen, Gaetano Thiene, Alessandra Rampazzo, Cristina Basso, Barbara Bauce, Alessandra Lorenzon, Gianluca Occhi
BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disease associated with point mutations in genes encoding for cardiac desmosome proteins. Conventional mutation screening is positive in ≈50% of probands. Copy number variations (CNVs) have recently been linked to AC pointing to the need to determine the prevalence of CNVs in desmosomal genes and to evaluate disease penetrance by cosegregation analysis in family members. METHODS AND RESULTS: A total of 160 AC genotype-negative probands for 5 AC desmosomal genes by conventional mutation screening underwent multiplex ligation-dependent probe amplification...
October 2017: Circulation. Arrhythmia and Electrophysiology
Roy A Quinlan, Nicole Schwarz, Reinhard Windoffer, Christine Richardson, Tim Hawkins, Joshua A Broussard, Kathleen J Green, Rudolf E Leube
Textbook images of keratin intermediate filament (IF) networks in epithelial cells and the functional compromization of the epidermis by keratin mutations promulgate a mechanical role for this important cytoskeletal component. In stratified epithelia, keratin filaments form prominent radial spokes that are focused onto cell-cell contact sites, i.e. the desmosomes. In this Hypothesis, we draw attention to a subset of keratin filaments that are apposed to the plasma membrane. They form a rim of filaments interconnecting the desmosomes in a circumferential network...
October 15, 2017: Journal of Cell Science
Jennifer Karmouch, Qiong Q Zhou, Christina Y Miyake, Raffaella Lombardi, Kai Kretzschmar, Marie Bannier-Hélaouët, Hans Clevers, Xander H T Wehrens, James T Willerson, Ali J Marian
RATIONALE: Arrhythmogenic cardiomyopathy is caused primarily by mutations in genes encoding desmosome proteins. Ventricular arrhythmias are the cardinal and typically early manifestations, whereas myocardial fibroadiposis is the pathological hallmark. Homozygous DSP (desmoplakin) and JUP (junction protein plakoglobin) mutations are responsible for a subset of patients with arrhythmogenic cardiomyopathy who exhibit cardiac arrhythmias and dysfunction, palmoplanter keratosis, and hair abnormalities (cardiocutaneous syndromes)...
December 8, 2017: Circulation Research
Edgar T Hoorntje, Wouter P Te Rijdt, Cynthia A James, Kalliopi Pilichou, Cristina Basso, Daniel P Judge, Connie R Bezzina, J Peter van Tintelen
Arrhythmogenic cardiomyopathy (ACM) is a rare, heritable heart disease characterized by fibro-fatty replacement of the myocardium and a high degree of electric instability. It was first thought to be a congenital disorder, but is now regarded as a dystrophic heart muscle disease that develops over time. There is no curative treatment and current treatment strategies focus on attenuating the symptoms, slowing disease progression, and preventing life-threatening arrhythmias and sudden cardiac death. Identification of mutations in genes encoding desmosomal proteins and in other genes has led to insights into the disease pathogenesis and greatly facilitated identification of family members at risk...
October 1, 2017: Cardiovascular Research
Alessandra Lorenzon, Martina Calore, Giulia Poloni, Leon J De Windt, Paola Braghetta, Alessandra Rampazzo
Wnt/β-catenin signaling pathway plays essential roles in heart development as well as cardiac tissue homoeostasis in adults. Abnormal regulation of this signaling pathway is linked to a variety of cardiac disease conditions, including hypertrophy, fibrosis, arrhythmias, and infarction. Recent studies on genetically modified cellular and animal models document a crucial role of Wnt/β-catenin signaling in the molecular pathogenesis of arrhythmogenic cardiomyopathy (AC), an inherited disease of intercalated discs, typically characterized by ventricular arrhythmias and progressive substitution of the myocardium with fibrofatty tissue...
September 1, 2017: Oncotarget
Sami Qadri, Olli Anttonen, Juho Viikilä, Eija H Seppälä, Samuel Myllykangas, Tero-Pekka Alastalo, Miia Holmström, Tiina Heliö, Juha W Koskenvuo
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease, involving changes in ventricular myocardial tissue and leading to fatal arrhythmias. Mutations in desmosomal genes are thought to be the main cause of ARVC. However, the exact molecular genetic etiology of the disease still remains largely inconclusive, and this along with large variabilities in clinical manifestations complicate clinical diagnostics. CASE PRESENTATION: We report two families (n = 20) in which a desmoglein-2 (DSG2) missense variant c...
August 17, 2017: BMC Medical Genetics
Simona Magi, Vincenzo Lariccia, Marta Maiolino, Salvatore Amoroso, Santo Gratteri
Sudden cardiac death (SCD) describes a natural and unexpected death from cardiac causes occurring within a short period of time (generally within 1 h of symptom onset) in the absence of any other potentially lethal condition. Most SCD-related diseases have a genetic basis; in particular congenital cardiac channelopathies and cardiomyopathies have been described as leading causes of SCD. Congenital cardiac channelopathies are primary electric disorders caused by mutations affecting genes encoding cardiac ion channels or associated proteins, whereas cardiomyopathies are related to mutations in genes encoding several categories of proteins, including those of sarcomeres, desmosomes, the cytoskeleton, and the nuclear envelope...
August 15, 2017: Journal of Biomedical Science
Joel Fedida, Veronique Fressart, Philippe Charron, Elodie Surget, Tiphaine Hery, Pascale Richard, Erwan Donal, Boris Keren, Guillaume Duthoit, Françoise Hidden-Lucet, Eric Villard, Estelle Gandjbakhch
BACKGROUND: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is an inherited cardiomyopathy mainly caused by heterozygous desmosomal gene mutations, the major gene being PKP2. The genetic cause remains unknown in ~50% of probands with routine desmosomal gene screening. The aim of this study was to assess the diagnostic accuracy of whole exome sequencing (WES) in ARVC/D with negative genetic testing. METHODS: WES was performed in 22 patients, all without a mutation identified in desmosomal genes...
2017: PloS One
Elise L Kessler, Peter Gj Nikkels, Toon Ab van Veen
Dilated cardiomyopathy (DCM) leads to disturbed contraction and force transduction, and is associated with substantial mortality in all age groups. Involvement of a disrupted composition of the intercalated disc (ID) has been reported. However, in children, little is established about such subcellular changes during disease, because of the pathological mix-up with the ongoing cardiac maturation. This leaves maladaptive remodeling often undetected. We aimed at illustrating subcellular alterations in children diagnosed with DCM compared to age-matched controls, focusing on ID proteins known to be crucially stable under healthy conditions and destabilized during cardiac injury in adults...
September 2017: Human Pathology
Marina Cerrone, Jerome Montnach, Xianming Lin, Yan-Ting Zhao, Mingliang Zhang, Esperanza Agullo-Pascual, Alejandra Leo-Macias, Francisco J Alvarado, Igor Dolgalev, Thomas V Karathanos, Kabir Malkani, Chantal J M Van Opbergen, Joanne J A van Bavel, Hua-Qian Yang, Carolina Vasquez, David Tester, Steven Fowler, Fengxia Liang, Eli Rothenberg, Adriana Heguy, Gregory E Morley, William A Coetzee, Natalia A Trayanova, Michael J Ackerman, Toon A B van Veen, Hector H Valdivia, Mario Delmar
Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell-cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling. Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for Ankyrin-B), Cacna1c (coding for CaV 1...
July 24, 2017: Nature Communications
Laura Padrón-Barthe, Fernando Domínguez, Pablo Garcia-Pavia, Enrique Lara-Pezzi
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetically-determined cardiac heart muscle disorder characterized by fibro-fatty replacement of the myocardium that results in heart failure and sudden cardiac death (SCD), predominantly in young males. The disease is often caused by mutations in genes encoding proteins of the desmosomal complex, with a significant minority caused by mutations in non-desmosomal proteins. Existing treatment options are based on SCD prevention with the implantable cardioverter defibrillator, antiarrhythmic drugs, and anti-heart failure medication...
September 2017: Basic Research in Cardiology
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