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Desmosome mutation

Seiko Ohno
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by degeneration of the right ventricle and ventricular tachycardia originating from the right ventricle. Additionally, the disease is an inherited cardiomyopathy that mainly follows the autosomal dominant pattern. More than 10 genes have been reported as causative genes for ARVC, and more than half of ARVC patients carry mutations in desmosome related genes. The desmosome is one of the structures involved in cell adhesion and its disruption leads to various diseases, including a skin disease called pemphigus...
October 2016: Journal of Arrhythmia
Štěpán Havránek, Tomáš Paleček, Petr Kuchynka, Ivana Vítková
Arrhythmogenic left ventricular cardiomyopathy (ALVC) is a rare condition characterised by progressive fibrofatty replacement of the myocardium of the left ventricle in combination with arrhythmias of left ventricular origin. ALVC has been linked to autosomal dominant mutations of genes encoding desmosomal proteins, similarly to the classic arrhythmogenic right ventricular cardiomyopathy with which it also shares pathological and prognostic features. It seems that isolated left or right ventricular abnormalities represent two extremes of the spectrum of clinical manifestations of a single disease: arrhythmogenic cardiomyopathy...
2016: Vnitr̆ní Lékar̆ství
Brett J Roberts, Robert A Svoboda, Andrew M Overmiller, Joshua D Lewis, Andrew P Kowalczyk, My G Mahoney, Keith R Johnson, James K Wahl
Desmosomes are prominent adhesive junctions present between many epithelial cells as well as cardiomyocytes. The mechanisms controlling desmosome assembly and remodeling in epithelial and cardiac tissue are poorly understood. We recently identified protein palmitoylation as a mechanism regulating desmosome dynamics. In this study we have focused on the palmitoylation of the desmosomal cadherin, desmoglein-2 (Dsg2), and characterized the role that palmitoylation of Dsg2 plays in its localization and stability in cultured cells...
October 4, 2016: Journal of Biological Chemistry
Deniz Akdis, Corinna Brunckhorst, Firat Duru, Ardan M Saguner
This overview gives an update on the molecular mechanisms, clinical manifestations, diagnosis and therapy of arrhythmogenic cardiomyopathy (ACM). ACM is mostly hereditary and associated with mutations in genes encoding proteins of the intercalated disc. Three subtypes have been proposed: the classical right-dominant subtype generally referred to as ARVC/D, biventricular forms with early biventricular involvement and left-dominant subtypes with predominant LV involvement. Typical symptoms include palpitations, arrhythmic (pre)syncope and sudden cardiac arrest due to ventricular arrhythmias, which typically occur in athletes...
August 2016: Arrhythmia & Electrophysiology Review
Mimount Bourfiss, Anneline S J M Te Riele, Thomas P Mast, Maarten J Cramer, Jeroen F VAN DER Heijden, Toon A B VAN Veen, Peter Loh, Dennis Dooijes, Richard N W Hauer, Birgitta K Velthuis
INTRODUCTION: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is associated with desmosomal mutations. Although desmosomal disruption affects both ventricles and atria, little is known about atrial involvement in ARVD/C. OBJECTIVE: To describe the extent and clinical significance of structural atrial involvement and atrial arrhythmias (AA) in ARVD/C stratified by genotype. METHODS: We included 71 patients who met ARVD/C Task Force Criteria and underwent cardiac magnetic resonance (CMR) imaging and molecular genetic analysis...
October 6, 2016: Journal of Cardiovascular Electrophysiology
Manuela Pigors, Ofer Sarig, Lisa Heinz, Vincent Plagnol, Judith Fischer, Janan Mohamad, Natalia Malchin, Shefali Rajpopat, Monia Kharfi, Giles G Lestringant, Eli Sprecher, David P Kelsell, Diana C Blaydon
SERPINS comprise a large and functionally diverse family of serine protease inhibitors. Here, we report three unrelated families with loss-of-function mutations in SERPINB8 in association with an autosomal-recessive form of exfoliative ichthyosis. Whole-exome sequencing of affected individuals from a consanguineous Tunisian family and a large Israeli family revealed a homozygous frameshift mutation, c.947delA (p.Lys316Serfs(∗)90), and a nonsense mutation, c.850C>T (p.Arg284(∗)), respectively. These two mutations are located in the last exon of SERPINB8 and, hence, would not be expected to lead to nonsense-mediated decay of the mRNA; nonetheless, both mutations are predicted to lead to loss of the reactive site loop of SERPINB8, which is crucial for forming the SERPINB8-protease complex...
August 4, 2016: American Journal of Human Genetics
Ryan E Fecteau, Jianping Kong, Adam Kresak, Wendy Brock, Yeunjoo Song, Hisashi Fujioka, Robert Elston, Joseph E Willis, John P Lynch, Sanford D Markowitz, Kishore Guda, Amitabh Chak
Importance: Esophageal adenocarcinoma and its precursor lesion Barrett esophagus have seen a dramatic increase in incidence over the past 4 decades yet marked genetic heterogeneity of this disease has precluded advances in understanding its pathogenesis and improving treatment. Objective: To identify novel disease susceptibility variants in a familial syndrome of esophageal adenocarcinoma and Barrett esophagus, termed familial Barrett esophagus, by using high-throughput sequencing in affected individuals from a large, multigenerational family...
October 1, 2016: JAMA Oncology
Javier Moncayo-Arlandi, Eduard Guasch, Maria Sanz, Marta Casado, Nahuel Aquiles García, Lluis Mont, Marta Sitges, Ralph Knöll, Byambajav Buyandelger, Campuzano Oscar, Antonio Diez-Juan, Ramon Brugada
Arrhythmogenic cardiomyopathy (ACM) is a disorder characterized by a progressive ventricular myocardial replacement by fat and fibrosis which lead to ventricular arrhythmias and sudden cardiac death. Mutations in the desmosomal gene Plakophilin-2 (PKP2) accounts for >40% of all known mutations, generally causing a truncated protein. In a PKP2 truncated mouse model, we hypothesize that content of transgene, endurance training and aging will be determinant in disease progression. In addition, we investigated the molecular defects associated with the phenotype in this model...
July 12, 2016: Human Molecular Genetics
Jackson J Liang, Martha Grogan, Michael J Ackerman
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an uncommon cardiomyopathy most classically associated with mutations in genes encoding desmosomal proteins. Recent literature has identified mutations in several non-desmosomal proteins including lamins that may result in the ARVC phenotype. We describe a patient who discovered her own pathogenic LMNA mutation that offered a unifying diagnosis explaining her ARVC and Charcot-Marie-Tooth phenotypes as well as musculoskeletal abnormalities. Suspicion for LMNA-mediated cardiomyopathy should arise in patients with extracardiac manifestations of laminopathies and testing for specific gene mutations may be helpful in establishing an unifying diagnosis...
July 2016: Journal of Cardiovascular Electrophysiology
Frauke Völlner, Jawahir Ali, Nina Kurrle, Yvonne Exner, Rüdiger Eming, Michael Hertl, Antje Banning, Ritva Tikkanen
Desmosomes are adhesion plaques that mediate cell-cell adhesion in many tissues, including the epidermis, and generate mechanical resistance to tissues. The extracellular domains of desmosomal cadherin proteins, desmogleins and desmocollins, are required for the interaction with cadherins of the neighbouring cells, whereas their cytoplasmic tails associate with cytoplasmic proteins which mediate connection to intermediate filaments. Disruption of desmosomal adhesion by mutations, autoantibodies or bacterial toxins results in severe human disorders of e...
2016: Scientific Reports
Jan Novak, Alessandro Zorzi, Silvia Castelletti, Antonis Pantasis, Ilaria Rigato, Domenico Corrado, William Mckenna, Pier D Lambiase
AIMS: The differentiation between idiopathic right ventricular outflow tract (RVOT) arrhythmias and early arrhythmogenic right ventricular cardiomyopathy (ARVC) can be challenging. We aimed to assess whether QRS morphological features and coupling interval of ventricular ectopic beats (VEBs) can improve differentiation between the two conditions. METHODS AND RESULTS: Twenty desmosomal-gene mutation carriers (13 females, mean age 43 years) with no or mild ARVC phenotypic expression and 33 age- and sex-matched subjects with idiopathic RVOT arrhythmias were studied...
June 23, 2016: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
Takahisa Kuga, Mitsuho Sasaki, Toshinari Mikami, Yasuo Miake, Jun Adachi, Maiko Shimizu, Youhei Saito, Minako Koura, Yasunori Takeda, Junichiro Matsuda, Takeshi Tomonaga, Yuji Nakayama
FAM83H is essential for the formation of dental enamel because a mutation in the FAM83H gene causes amelogenesis imperfecta (AI). We previously reported that the overexpression of FAM83H often occurs and disorganizes the keratin cytoskeleton in colorectal cancer cells. We herein show that FAM83H regulates the organization of the keratin cytoskeleton and maintains the formation of desmosomes in ameloblastoma cells. FAM83H is expressed and localized on keratin filaments in human ameloblastoma cell lines and in mouse ameloblasts and epidermal germinative cells in vivo...
2016: Scientific Reports
Argelia Medeiros-Domingo, Ardan M Saguner, István Magyar, Angela Bahr, Deniz Akdis, Corinna Brunckhorst, Firat Duru, Wolfgang Berger
AIMS: To evaluate potential differences in the genetic profile of cases with 'definite', 'borderline', and 'possible' arrhythmogenic right ventricular cardiomyopathy (ARVC) phenotype by 2010 task force criteria using a custom genetic panel after whole-exome analysis. METHODS AND RESULTS: We performed whole-exome sequencing in 14 cases with the clinical diagnosis ARVC using an 'Illumina HighSeq 2000' system. We presented our initial results focused on 96 known cardiomyopathy and channelopathy genes...
May 18, 2016: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
Stephen P Chelko, Angeliki Asimaki, Peter Andersen, Djahida Bedja, Nuria Amat-Alarcon, Deeptankar DeMazumder, Ravirasmi Jasti, Calum A MacRae, Remo Leber, Andre G Kleber, Jeffrey E Saffitz, Daniel P Judge
Arrhythmogenic cardiomyopathy (ACM) is characterized by redistribution of junctional proteins, arrhythmias, and progressive myocardial injury. We previously reported that SB216763 (SB2), annotated as a GSK3β inhibitor, reverses disease phenotypes in a zebrafish model of ACM. Here, we show that SB2 prevents myocyte injury and cardiac dysfunction in vivo in two murine models of ACM at baseline and in response to exercise. SB2-treated mice with desmosome mutations showed improvements in ventricular ectopy and myocardial fibrosis/inflammation as compared with vehicle-treated (Veh-treated) mice...
April 21, 2016: JCI Insight
Lei Huang, Shuangbo Tang, Longyun Peng, Yili Chen, Jianding Cheng
Plakophilin-2 (PKP2) variants could produce a phenotype of Brugada syndrome (BrS), which seems to be most likely the same allelic disorder as some sudden unexplained nocturnal death syndrome (SUNDS). All coding regions of PKP2 gene in 119 SUNDS victims were genetically screened using PCR and direct Sanger sequencing methods. Three novel mutations (p.Ala159Thr, p.Val200Val, and p.Gly265Glu), one novel rare polymorphism (p.Thr723Thr), and eight reported polymorphisms were identified. A compound mutation (p.Ala159Thr and p...
May 2016: Journal of Forensic Sciences
Raffaella Lombardi, Suet Nee Chen, Alessandra Ruggiero, Priyatansh Gurha, Grazyna Z Czernuszewicz, James T Willerson, Ali J Marian
RATIONALE: Mutations in desmosome proteins cause arrhythmogenic cardiomyopathy (AC), a disease characterized by excess myocardial fibroadipocytes. Cellular origin(s) of fibroadipocytes in AC is unknown. OBJECTIVE: To identify the cellular origin of adipocytes in AC. METHODS AND RESULTS: Human and mouse cardiac cells were depleted from myocytes and flow sorted to isolate cells expressing platelet-derived growth factor receptor-α and exclude those expressing other lineage and fibroblast markers (CD32, CD11B, CD45, Lys76, Ly(-6c) and Ly(6c), thymocyte differentiation antigen 1, and discoidin domain receptor 2)...
June 24, 2016: Circulation Research
Valeria Mezzano, Yan Liang, Adam T Wright, Robert C Lyon, Emily Pfeiffer, Michael Y Song, Yusu Gu, Nancy D Dalton, Melvin Scheinman, Kirk L Peterson, Sylvia M Evans, Steven Fowler, Marina Cerrone, Andrew D McCulloch, Farah Sheikh
AIMS: Current mechanisms driving cardiac pacemaker function have focused on ion channel and gap junction channel function, which are essential for action potential generation and propagation between pacemaker cells. However, pacemaker cells also harbour desmosomes that structurally anchor pacemaker cells to each other in tissue, but their role in pacemaker function remains unknown. METHODS AND RESULTS: To determine the role of desmosomes in pacemaker function, we generated a novel mouse model harbouring cardiac conduction-specific ablation (csKO) of the central desmosomal protein, desmoplakin (DSP) using the Hcn4-Cre-ERT2 mouse line...
August 1, 2016: Cardiovascular Research
Kalliopi Pilichou, Gaetano Thiene, Barbara Bauce, Ilaria Rigato, Elisabetta Lazzarini, Federico Migliore, Martina Perazzolo Marra, Stefania Rizzo, Alessandro Zorzi, Luciano Daliento, Domenico Corrado, Cristina Basso
Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and progressive dystrophy of the ventricular myocardium with fibro-fatty replacement. Due to an estimated prevalence of 1:2000-1:5000, AC is listed among rare diseases. A familial background consistent with an autosomal-dominant trait of inheritance is present in most of AC patients; recessive variants have also been reported, either or not associated with palmoplantar keratoderma and woolly hair...
2016: Orphanet Journal of Rare Diseases
Keiko Sonoda, Seiko Ohno, Sou Otuki, Koichi Kato, Nobue Yagihara, Hiroshi Watanabe, Takeru Makiyama, Tohru Minamino, Minoru Horie
AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease mainly caused by desmosome gene mutations. The genetic culprit, however, remains elusive in ∼50% of ARVC patients. One of the reasons for missing genetic abnormalities is the difficulty in detecting large deletions/duplications, which are called as copy number variation (CNV) by the Sanger sequencing method. This study aimed to identify CNVs in PKP2 and a part of other desmosome genes in ARVC patients. METHODS AND RESULTS: The study cohort consisted of 71 ARVC probands who were diagnosed as definite or borderline cases based on 2010 Task Force Criteria...
March 22, 2016: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
Wouter P Te Rijdt, J Peter van Tintelen, Aryan Vink, Allard C van der Wal, Rudolf A de Boer, Maarten P van den Berg, Albert J H Suurmeijer
AIMS: The non-desmosomal phospholamban PLN p.Arg14del mutation was identified in patients diagnosed with dilated cardiomyopathy (DCM) and/or arrhythmogenic cardiomyopathy (ACM). We aimed to investigate whether this mutation leads to aggregation, aggresome formation and autophagy of mutant PLN protein. METHODS AND RESULTS: We studied 20 complete heart specimens of PLN p.Arg14del mutation carriers [mean age 48 ± 15 years; 55% males], either from autopsies or from explants...
October 2016: Histopathology
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