267 results on '"Desmoglein-2"'
Search Results
252. Desmoglein-2 and Desmocollin-2 Mutations in Dutch Arrhythmogenic Right Ventricular Dysplasia/Cardiomypathy Patients Results From a Multicenter Study
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Marcel M.A.M. Mannens, Maarten P. van den Berg, Jan D. H. Jongbloed, Zahurul A. Bhuiyan, Moniek G.P.J. Cox, Luz M. Rodriguez, Ans C.P. Wiesfeld, J. Peter van Tintelen, Marcel R. Nelen, Paola M. Lombardi, Isabelle C. Van Gelder, Richard N.W. Hauer, Roselie Jongbloed, Albert J. H. Suurmeijer, Arthur A.M. Wilde, Hennie Bikker, Jasper J. van der Smagt, Meyke Schouten, Marleen van Wolferen, Human Genetics, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Other Research, ARD - Amsterdam Reproduction and Development, Cardiology, Other departments, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Cardiovascular Centre (CVC)
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Adult ,Male ,Proband ,MISSENSE MUTATIONS ,EXPRESSION ,Heterozygote ,medicine.medical_specialty ,PLAKOGLOBIN CAUSES ,Adolescent ,Desmoglein-2 ,Biology ,Compound heterozygosity ,medicine.disease_cause ,arrhythmia ,FAMILIES ,Cohort Studies ,Young Adult ,Internal medicine ,medicine ,Humans ,Missense mutation ,desmosomes ,genetics ,PLAKOPHILIN-2 MUTATIONS ,DYSPLASIA ,Arrhythmogenic Right Ventricular Dysplasia ,Genetics (clinical) ,Netherlands ,Desmocollins ,Mutation ,SPECTRUM ,Desmoglein 2 ,DSC2 ,CARDIOMYOPATHY ,Middle Aged ,medicine.disease ,GENE ,Pedigree ,Arrhythmogenic right ventricular dysplasia ,NAXOS-DISEASE ,Dysplasia ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,Plakophilins - Abstract
Background— This study aimed to evaluate the prevalence and type of mutations in the major desmosomal genes, Plakophilin-2 ( PKP2 ), Desmoglein-2 ( DSG2 ), and Desmocollin-2 ( DSC2 ), in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We also aimed to distinguish relevant clinical and ECG parameters. Methods and Results— Clinical evaluation was performed according to the Task Force Criteria (TFC). We analyzed the genes in (a) 57 patients who fulfilled the ARVD/C TFC (TFC+), (b) 28 patients with probable ARVD/C (1 major and 1 minor, or 3 minor criteria), and (c) 31 patients with 2 minor or 1 major criteria. In the TFC+ ARVD/C group, 23 patients (40%) had PKP2 mutations, 4 (7%) had DSG2 mutations, and 1 patient (2%) carried a mutation in DSC2 , whereas 1 patient (2%) had a mutation in both DSG2 and DSC2 . Among the DSG2 and DSC2 mutation-positive TFC+ ARVD/C probands, 2 carried compound heterozygous mutations and 1 had digenic mutations. In probable ARVD/C patients and those with 2 minor or 1 major criteria for ARVD/C, mutations were less frequent and they were all heterozygous. Negative T waves in the precordial leads were observed more ( P PKP2 mutation carriers. Conclusions— Mutations in DSG2 and DSC2 are together less prevalent (10%) than PKP2 mutations (40%) in Dutch TFC+ ARVD/C patients. Interestingly, biallelic or digenic DSC2 and/or DSG2 mutations are frequently identified in TFC+ ARVD/C patients, suggesting that a single mutation is less likely to cause a full-blown ARVD/C phenotype. Negative T waves on ECG were prevalent among mutation carriers ( P
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- 2009
253. Molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy
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Hendrik Milting and Baerbel Klauke
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medicine.medical_specialty ,business.industry ,Molecular genetics ,Internal medicine ,medicine ,Cardiology ,Cardiomyopathy ,Desmoglein-2 ,General Medicine ,Cardiology and Cardiovascular Medicine ,business ,medicine.disease ,Arrhythmogenic right ventricular dysplasia - Published
- 2008
254. E713K in desmoglein-2 and arrhythmogenic right ventricular dysplasia/cardiomyopathy
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Daniel P. Judge
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medicine.medical_specialty ,business.industry ,Internal medicine ,Cardiology ,medicine ,Cardiomyopathy ,Desmoglein-2 ,General Medicine ,Cardiology and Cardiovascular Medicine ,business ,medicine.disease ,Arrhythmogenic right ventricular dysplasia - Published
- 2008
255. Monoclonal Antibodies 3B11, 20G1, 7H9, 19B9, 10D2, 13B11 Against Desmoglein-2
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James K. Wahl
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biology ,medicine.drug_class ,business.industry ,Immunology ,medicine ,biology.protein ,Immunology and Allergy ,Desmoglein-2 ,Monoclonal antibody ,business ,Virology ,Primary and secondary antibodies - Published
- 2008
256. c-Src/Cav1-dependent activation of the EGFR by Dsg2.
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Overmiller AM, McGuinn KP, Roberts BJ, Cooper F, Brennan-Crispi DM, Deguchi T, Peltonen S, Wahl JK 3rd, and Mahoney MG
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- CSK Tyrosine-Protein Kinase, Caveolin 1 genetics, Cell Line, Tumor, Cell Movement physiology, Cell Proliferation physiology, Desmoglein 2 genetics, Desmoglein 2 metabolism, ErbB Receptors genetics, ErbB Receptors metabolism, Fibrosarcoma genetics, Fibrosarcoma metabolism, Humans, Membrane Microdomains enzymology, Membrane Microdomains metabolism, Signal Transduction, Skin Neoplasms genetics, Skin Neoplasms metabolism, Up-Regulation, src-Family Kinases genetics, Caveolin 1 metabolism, Desmoglein 2 biosynthesis, ErbB Receptors biosynthesis, src-Family Kinases metabolism
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The desmosomal cadherin, desmoglein 2 (Dsg2), is deregulated in a variety of human cancers including those of the skin. When ectopically expressed in the epidermis of transgenic mice, Dsg2 activates multiple mitogenic signaling pathways and increases susceptibility to tumorigenesis. However, the molecular mechanism responsible for Dsg2-mediated cellular signaling is poorly understood. Here we show overexpression as well as co-localization of Dsg2 and EGFR in cutaneous SCCs in vivo. Using HaCaT keratinocytes, knockdown of Dsg2 decreases EGFR expression and abrogates the activation of EGFR, c-Src and Stat3, but not Erk1/2 or Akt, in response to EGF ligand stimulation. To determine whether Dsg2 mediates signaling through lipid microdomains, sucrose density fractionation illustrated that Dsg2 is recruited to and displaces Cav1, EGFR and c-Src from light density lipid raft fractions. STED imaging confirmed that the presence of Dsg2 disperses Cav1 from the cell-cell borders. Perturbation of lipid rafts with the cholesterol-chelating agent MβCD also shifts Cav1, c-Src and EGFR out of the rafts and activates signaling pathways. Functionally, overexpression of Dsg2 in human SCC A431 cells enhances EGFR activation and increases cell proliferation and migration through a c-Src and EGFR dependent manner. In summary, our data suggest that Dsg2 stimulates cell growth and migration by positively regulating EGFR level and signaling through a c-Src and Cav1-dependent mechanism using lipid rafts as signal modulatory platforms., Competing Interests: The authors declare that there are no competing financial interests in relation to the work described.
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- 2016
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257. Desmoglein-2 during pregnancy and its role in the evolution of viviparity in a marsupial (Sminthopsis crassicaudata; Dasyuridae).
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Dudley JS, Murphy CR, Thompson MB, and McAllan BM
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- Animals, Biological Evolution, Blotting, Western, Cell Membrane chemistry, Cell Membrane ultrastructure, Desmosomes ultrastructure, Embryo Implantation, Epithelial Cells chemistry, Epithelial Cells ultrastructure, Female, Fluorescent Antibody Technique, Marsupialia anatomy & histology, Microscopy, Electron, Placentation, Pregnancy, Desmoglein 2 analysis, Marsupialia physiology, Uterus chemistry, Uterus ultrastructure
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Attachment of the blastocyst and formation of the placenta during pregnancy is dependent on structural and cellular changes occurring in the uterine epithelium and in particular to the plasma membrane of these uterine cells. Desmosome expression decreases during pregnancy in eutherians and some squamates, presumably allowing for remodeling of the uterine epithelium and invasion of the trophoblast during implantation. Marsupials are a distinct mammalian amniote lineage of viviparity, with a short implantation or attachment period and varying levels of invasive placentation. To test the generality of changes to the uterine epithelium during pregnancy across mammals, we characterized the distribution of desmosomes in the uterine epithelial cells of a marsupial, Sminthopsis crassicaudata, using electron microscopy and immunohistochemistry. The absolute number of desmosomes along the lateral plasma membrane decreases during pregnancy and desmosomes are redistributed towards the apical region of the lateral plasma membrane as pregnancy proceeds, similar to what occurs during pregnancy in eutherian mammals. Despite the lower level of maternal investment in pregnancy and the noninvasive structure of fetal membranes in marsupials there are similarities in number and redistribution of desmosomes along the plasma membrane and changes to the morphology of the uterine epithelial cells suggesting that similar plasma membrane changes occur across all lineages of amniote vertebrates., (© 2014 Wiley Periodicals, Inc.)
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- 2015
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258. Constitutive desmoglein 2 expression by adnexal epithelia and basal cell carcinoma: Relation to the tumor cell origin
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Mikio Ohtsuka, Keiji Iwatsuki, Fumio Kaneko, Hitoshi Akiba, and Hiroshi Harada
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Pathology ,medicine.medical_specialty ,medicine ,Desmoglein-2 ,Tumor cells ,Basal cell carcinoma ,Dermatology ,Biology ,medicine.disease ,Molecular Biology ,Biochemistry - Published
- 1998
259. Galectin-3 regulates desmoglein-2 and intestinal epithelial intercellular adhesion.
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Jiang K, Rankin CR, Nava P, Sumagin R, Kamekura R, Stowell SR, Feng M, Parkos CA, and Nusrat A
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- Animals, Cell Adhesion, Cell Communication, Cell Line, Cell Proliferation, Epithelial Cells metabolism, Epithelium metabolism, Galactose chemistry, Gene Expression Regulation, Homeostasis, Humans, Lactose chemistry, Membrane Microdomains chemistry, Mice, Proteasome Endopeptidase Complex metabolism, Protein Structure, Tertiary, Proteomics, RNA, Small Interfering metabolism, Recombinant Proteins chemistry, Desmoglein 2 metabolism, Epithelial Cells cytology, Galectin 3 metabolism, Intestines cytology
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The desmosomal cadherins, desmogleins, and desmocollins mediate strong intercellular adhesion. Human intestinal epithelial cells express the desmoglein-2 isoform. A proteomic screen for Dsg2-associated proteins in intestinal epithelial cells identified a lectin referred to as galectin-3 (Gal3). Gal3 bound to N-linked β-galactosides in Dsg2 extracellular domain and co-sedimented with caveolin-1 in lipid rafts. Down-regulation of Gal3 protein or incubation with lactose, a galactose-containing disaccharide that competitively inhibits galectin binding to Dsg2, decreased intercellular adhesion in intestinal epithelial cells. In the absence of functional Gal3, Dsg2 protein was internalized from the plasma membrane and degraded in the proteasome. These results report a novel role of Gal3 in stabilizing a desmosomal cadherin and intercellular adhesion in intestinal epithelial cells.
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- 2014
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260. Colon tumour secretopeptidome: insights into endogenous proteolytic cleavage events in the colon tumour microenvironment.
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Greening DW, Kapp EA, Ji H, Speed TP, and Simpson RJ
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- Amino Acid Sequence, Cell Line, Tumor, Chromatography, High Pressure Liquid, Colon pathology, Colonic Neoplasms pathology, GPI-Linked Proteins analysis, GPI-Linked Proteins metabolism, Humans, Membrane Glycoproteins analysis, Membrane Glycoproteins metabolism, Molecular Sequence Data, Peptides analysis, Protein Processing, Post-Translational, Proteolysis, Proteome analysis, Proteomics, Secretory Pathway, Tandem Mass Spectrometry, Colon metabolism, Colonic Neoplasms metabolism, Peptides metabolism, Proteome metabolism, Tumor Microenvironment
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The secretopeptidome comprises endogenous peptides derived from proteins secreted into the tumour microenvironment through classical and non-classical secretion. This study characterised the low-Mr (<3kDa) component of the human colon tumour (LIM1215, LIM1863) secretopeptidome, as a first step towards gaining insights into extracellular proteolytic cleavage events in the tumour microenvironment. Based on two biological replicates, this secretopeptidome isolation strategy utilised differential centrifugal ultrafiltration in combination with analytical RP-HPLC and nanoLC-MS/MS. Secreted peptides were identified using a combination of Mascot and post-processing analyses including MSPro re-scoring, extended feature sets and Percolator, resulting in 474 protein identifications from 1228 peptides (≤1% q-value, ≤5% PEP) - a 36% increase in peptide identifications when compared with conventional Mascot (homology ionscore thresholding). In both colon tumour models, 122 identified peptides were derived from 41 cell surface protein ectodomains, 23 peptides (12 proteins) from regulated intramembrane proteolysis (RIP), and 12 peptides (9 proteins) generated from intracellular domain proteolysis. Further analyses using the protease/substrate database MEROPS, (http://merops.sanger.ac.uk/), revealed 335 (71%) proteins classified as originating from classical/non-classical secretion, or the cell membrane. Of these, peptides were identified from 42 substrates in MEROPS with defined protease cleavage sites, while peptides generated from a further 205 substrates were fragmented by hitherto unknown proteases. A salient finding was the identification of peptides from 88 classical/non-classical secreted substrates in MEROPS, implicated in tumour progression and angiogenesis (FGFBP1, PLXDC2), cell-cell recognition and signalling (DDR1, GPA33), and tumour invasiveness and metastasis (MACC1, SMAGP); the nature of the proteases responsible for these proteolytic events is unknown. To confirm reproducibility of peptide fragment abundance in this study, we report the identification of a specific cleaved peptide fragment in the secretopeptidome from the colon-specific GPA33 antigen in 4/14 human CRC models. This improved secretopeptidome isolation and characterisation strategy has extended our understanding of endogenous peptides generated through proteolysis of classical/non-classical secreted proteins, extracellular proteolytic processing of cell surface membrane proteins, and peptides generated through RIP. The novel peptide cleavage site information in this study provides a useful first step in detailing proteolytic cleavage associated with tumourigenesis and the extracellular environment. This article is part of a Special Issue entitled: An Updated Secretome., (Copyright © 2013 Elsevier B.V. All rights reserved.)
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- 2013
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261. Compound and Digenic Heterozygosity Contributes to Arrhythmogenic Right Ventricular Cardiomyopathy
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Xu, T, Yang, Z, Vatta, M, Rampazzo, Alessandra, Beffagna, Giorgia, Pilichou, Kalliopi, Scherer, S, Phd, Saffitz, J, Kravitz, J, Zareba, W, Danieli, GIAN ANTONIO, Lorenzon, A, Nava, Andrea, Bauce, Barbara, Thiene, Gaetano, Basso, Cristina, Calkins, H, Gear, K, Marcus, F, and Towbin, J.
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Adult ,Male ,cardiomyopathies ,Heterozygote ,Adolescent ,Plakoglobin ,Desmoglein-2 ,030204 cardiovascular system & hematology ,genetic mutations ,Compound heterozygosity ,Article ,Right ventricular cardiomyopathy ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,desmosomes ,Child ,Arrhythmogenic Right Ventricular Dysplasia ,030304 developmental biology ,Genetics ,0303 health sciences ,DSC2 ,biology ,business.industry ,Desmoplakin ,Middle Aged ,medicine.disease ,Penetrance ,Pedigree ,3. Good health ,Arrhythmogenic right ventricular dysplasia ,biology.protein ,intercalated disks ,Female ,business ,Cardiology and Cardiovascular Medicine ,arrhythmias - Abstract
Objectives The aim of this study was to define the genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Background Arrhythmogenic right ventricular cardiomyopathy, characterized by right ventricular fibrofatty replacement and arrhythmias, causes sudden death. Autosomal dominant inheritance, reduced penetrance, and 7 desmosome-encoding causative genes are known. The basis of low penetrance is poorly understood. Methods Arrhythmogenic right ventricular cardiomyopathy probands and family members were enrolled, blood was obtained, lymphoblastoid cell lines were immortalized, deoxyribonucleic acid was extracted, polymerase chain reaction (PCR) amplification of desmosome-encoding genes was performed, PCR products were sequenced, and diseased tissue samples were studied for intercellular junction protein distribution with confocal immunofluorescence microscopy and antibodies against key proteins. Results We identified 21 variants in plakophilin-2(PKP2) in 38 of 198 probands (19%), including missense, nonsense, splice site, and deletion/insertion mutations. Pedigrees showed wide intra-familial variability (severe early-onset disease to asymptomatic individuals). In 9 of 38 probands, PKP2variants were identified that were encoded in trans(compound heterozygosity). The 38 probands hosting PKP2variants were screened for other desmosomal genes mutations; second variants (digenic heterozygosity) were identified in 16 of 38 subjects with PKP2variants (42%), including desmoplakin(DSP) (n = 6), desmoglein-2(DSG2) (n = 5), plakophilin-4(PKP4) (n = 1), and desmocollin-2(DSC2) (n = 1). Heterozygous mutations in non-PKP 2desmosomal genes occurred in 14 of 198 subjects (7%), including DSP(n = 4), DSG2(n = 5), DSC2(n = 3), and junctional plakoglobin(JUP) (n = 2). All variants occurred in conserved regions; none was identified in 700 ethnic-matched control subjects. Immunohistochemical analysis demonstrated abnormalities of protein architecture. Conclusions These data suggest that the genetic basis of ARVC includes reduced penetrance with compound and digenic heterozygosity. Disturbed junctional cytoarchitecture in subjects with desmosomal mutations confirms that ARVC is a disease of the desmosome and cell junction.
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262. Homo- and Heterotypic Cell Contacts in Malignant Melanoma Cells and Desmoglein 2 as a Novel Solitary Surface Glycoprotein
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Wiebke K. Peitsch, Steffen Rickelt, Berit Falkowska-Hansen, Christian Schmitt, Werner W. Franke, and Sergij Goerdt
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Keratinocytes ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Immunoelectron microscopy ,Cell ,Desmoglein-2 ,Cell Communication ,Dermatology ,Biology ,Biochemistry ,Desmoglein ,Cell Line, Tumor ,Cell Adhesion ,medicine ,Humans ,Cell adhesion ,Melanoma ,Molecular Biology ,Desmocollins ,Desmoglein 2 ,Cadherin ,Catenins ,Cell Biology ,Cadherins ,medicine.disease ,Molecular biology ,medicine.anatomical_structure ,Microscopy, Fluorescence ,Puncta adhaerentia ,Epidermis ,Desmogleins ,Plakophilins - Abstract
During progression of melanomas, a crucial role has been attributed to alterations of cell-cell adhesions, specifically, to a "cadherin switch" from E- to N-cadherin (cad). We have examined the adhesion of melanoma cells to each other and to keratinocytes. When different human melanoma cell lines were studied by protein analysis and immunofluorescence microscopy, six of eight lines contained N-cad, three E-cad, and five P-cad, and some lines had more than one cad. Surprisingly, two N-cad-positive lines, MeWo and C32, also contained desmoglein 2 (Dsg2), a desmosomal cad previously not reported for melanomas, whereas other desmosome-specific proteins were absent. This finding was confirmed by reverse transcriptase-PCR, immunoprecipitation, and matrix-assisted laser desorption ionization-time of flight analyses. Double-label confocal and immunoelectron microscopy showed N-cad, alpha- and beta-catenin in plaque-bearing puncta adhaerentia, whereas Dsg2 was distributed rather diffusely over the cell surface. In cocultures with HaCaT keratinocytes Dsg2 was found in heterotypic cell contact regions. Correspondingly, immunohistochemistry revealed Dsg2 in five of 10 melanoma metastases. Together, we show that melanoma cell adhesions are more heterogeneous than expected and that certain cells devoid of desmosomes contain Dsg2 in a non-junction-restricted form. Future studies will have to clarify the diagnostic and prognostic significance of these different adhesion protein subtypes.
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263. Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Is a Fully Penetrant, Lethal Arrhythmic Disorder Caused by a Missense Mutation in the TMEM43 Gene
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Anne S. Bassett, Barry Gallagher, Jörg-Detlef Drenckhahn, Lynn Morris-Larkin, Annika F.M. Haywood, Terry-Lynn Young, Vanessa M. French, Patrick S. Parfrey, Kathy Hodgkinson, Christine Kupprion, William J. McKenna, Kalina Ramadanova, Ludwig Thierfelder, Nancy D. Merner, and Sean Connors
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Male ,Protein Conformation ,DNA Mutational Analysis ,Penetrance ,030204 cardiovascular system & hematology ,0302 clinical medicine ,Missense mutation ,Genetics(clinical) ,Child ,Genetics (clinical) ,Arrhythmogenic Right Ventricular Dysplasia ,Genetics ,Aged, 80 and over ,0303 health sciences ,education.field_of_study ,Middle Aged ,Physical Chromosome Mapping ,3. Good health ,Arrhythmogenic right ventricular dysplasia ,Pedigree ,Female ,Chromosomes, Human, Pair 3 ,Adult ,medicine.medical_specialty ,Adolescent ,Population ,Molecular Sequence Data ,Mutation, Missense ,Desmoglein-2 ,Biology ,Right ventricular cardiomyopathy ,Article ,03 medical and health sciences ,Life Expectancy ,Sex Factors ,Internal medicine ,medicine ,Humans ,Amino Acid Sequence ,Genetic Testing ,education ,030304 developmental biology ,Aged ,Heart Failure ,DSC2 ,Genetic heterogeneity ,Myocardium ,Membrane Proteins ,medicine.disease ,Endocrinology - Abstract
Autosomal-dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) causes sudden cardiac death and is characterized by clinical and genetic heterogeneity. Fifteen unrelated ARVC families with a disease-associated haplotype on chromosome 3p (ARVD5) were ascertained from a genetically isolated population. Identification of key recombination events reduced the disease region to a 2.36 Mb interval containing 20 annotated genes. Bidirectional resequencing showed one rare variant in transmembrane protein 43 (TMEM43 1073C--T, S358L), was carried on all recombinant ARVD5 ancestral haplotypes from affected subjects and not found in population controls. The mutation occurs in a highly conserved transmembrane domain of TMEM43 and is predicted to be deleterious. Clinical outcomes in 257 affected and 151 unaffected subjects were compared, and penetrance was determined. We concluded that ARVC at locus ARVD5 is a lethal, fully penetrant, sex-influenced morbid disorder. Median life expectancy was 41 years in affected males compared to 71 years in affected females (relative risk 6.8, 95% CI 1.3-10.9). Heart failure was a late manifestation in survivors. Although little is known about the function of the TMEM43 gene, it contains a response element for PPAR gamma (an adipogenic transcription factor), which may explain the fibrofatty replacement of the myocardium, a characteristic pathological finding in ARVC.
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264. A non-canonical role for desmoglein-2 in endothelial cells: implications for neoangiogenesis
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Simon A. Koblar, Stan Gronthos, Samantha E. Boyle, Kelly L. Betterman, Angel F. Lopez, Andrew C.W. Zannettino, Kate A. Parham, Michaelia P. Cockshell, Claudine S. Bonder, Kay Khine Myo Min, Angela Peng, YouFang F. Zhang, Natasha L. Harvey, Lokugan S. Silva, M. Zahied Johan, Mark Shackleton, Paceman Szeto, Lisa M. Ebert, Lih Y. Tan, Andrew Ruszkiewicz, Ebert, Lisa M, Tan, Lih Y, Johan, M Zahied, Min, Kay Khine Myo, Cockshell, Michaelia P, Parham, Kate A, Betterman, Kelly L, Szeto, Paceman, Boyle, Samantha, Silva, Lokugan, Peng, Angela, Zhang, YouFang, Zannettino, Andrew CW, Gronthos, Stan, Koblar, Simon, Harvey, Natasha L, Lopez, Angel F, Shackleton, Mark, and Bonder, Claudine S
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Cancer Research ,endothelium ,Angiogenesis ,Physiology ,Clinical Biochemistry ,Hematopoietic stem and progenitor cells ,CD34 ,Neovascularization, Physiologic ,Biology ,endothelial progenitorcells ,Desmoglein ,Mice ,03 medical and health sciences ,Vasculogenesis ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,RNA, Messenger ,Endothelium ,RNA, Small Interfering ,Progenitor cell ,Cells, Cultured ,Endothelial progenitor cells ,Interleukin 3 ,Mice, Knockout ,Original Paper ,Desmoglein 2 ,Cadherin ,Endothelial Cells ,Cell Differentiation ,Hematopoietic Stem Cells ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,Endothelial stem cell ,030104 developmental biology ,Gene Knockdown Techniques ,Mouse models of neoangiogenesis ,hematopoietic stem and progenitorcells ,Models, Animal ,Female ,mouse models of neoangiogenesis ,DESMOGLEIN-2 - Abstract
Desmogleins (DSG) are a family of cadherin adhesion proteins that were first identified in desmosomes and provide cardiomyocytes and epithelial cells with the junctional stability to tolerate mechanical stress. However, one member of this family, DSG2, is emerging as a protein with additional biological functions on a broader range of cells. Here we reveal that DSG2 is expressed by non-desmosome-forming human endothelial progenitor cells as well as their mature counterparts [endothelial cells (ECs)] in human tissue from healthy individuals and cancer patients. Analysis of normal blood and bone marrow showed that DSG2 is also expressed by CD34+CD45dim hematopoietic progenitor cells. An inability to detect other desmosomal components, i.e., DSG1, DSG3 and desmocollin (DSC)2/3, on these cells supports a solitary role for DSG2 outside of desmosomes. Functionally, we show that CD34+CD45dimDSG2+ progenitor cells are multi-potent and pro-angiogenic in vitro. Using a ‘knockout-first’ approach, we generated a Dsg2 loss-of-function strain of mice (Dsg2lo/lo) and observed that, in response to reduced levels of Dsg2: (i) CD31+ ECs in the pancreas are hypertrophic and exhibit altered morphology, (ii) bone marrow-derived endothelial colony formation is impaired, (iii) ex vivo vascular sprouting from aortic rings is reduced, and (iv) vessel formation in vitro and in vivo is attenuated. Finally, knockdown of DSG2 in a human bone marrow EC line reveals a reduction in an in vitro angiogenesis assay as well as relocalisation of actin and VE-cadherin away from the cell junctions, reduced cell–cell adhesion and increased invasive properties by these cells. In summary, we have identified DSG2 expression in distinct progenitor cell subpopulations and show that, independent from its classical function as a component of desmosomes, this cadherin also plays a critical role in the vasculature. Electronic supplementary material The online version of this article (doi:10.1007/s10456-016-9520-y) contains supplementary material, which is available to authorized users.
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265. Dilated Cardiomyopathy Overview
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Hershberger RE, Jordan E, Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, and Amemiya A
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Unlabelled: The purpose of this overview is to increase clinician awareness of the genetic basis of dilated cardiomyopathy (DCM) and the benefits of early diagnosis and management to individuals with genetic DCM. The following are the goals of this overview., Goal 1: Define DCM., Goal 2: Identify the categories of DCM., Goal 3: Provide the evaluation strategy of a proband with nonsyndromic DCM., Goal 4: Provide a basic view of genetic risk assessment of at-risk asymptomatic relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome., (Copyright © 1993-2022, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.)
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- 1993
266. Arrhythmogenic right ventricular cardiomyopathy: Dysplasia, dystrophy, or myocarditis?
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Marialuisa Valente, Cristina Basso, Gaetano Thiene, Andrea Nava, Domenico Corrado, and Annalisa Angelini
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Adult ,Male ,medicine.medical_specialty ,Pathology ,Myocarditis ,Adolescent ,Cardiomyopathy ,Desmoglein-2 ,Sudden death ,Right ventricular cardiomyopathy ,Physiology (medical) ,Internal medicine ,Humans ,Medicine ,Aged ,DSC2 ,business.industry ,Arrhythmias, Cardiac ,Middle Aged ,medicine.disease ,Arrhythmogenic right ventricular dysplasia ,medicine.anatomical_structure ,Ventricle ,Cardiology ,Female ,Atrophy ,Cardiomyopathies ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a frequent cause of sudden death in young individuals and athletes. Although familial occurrence has been documented and a gene defect was recently localized on chromosome 14q23-q24 the etiopathogenesis of the disease is still obscure. Methods and Results A pathological study was conducted in 30 hearts with ARVC (age range, 15 to 65 years; mean, 28 years). In the 27 autopsy cases, the mode of death was sudden in 24 and congestive heart failure in 3. ECG, available in 19 cases, showed inverted T waves in the right precordial leads in 15 cases (79%) and ventricular arrhythmias in 15 (79%). Right ventricular aneurysms were present in 15 hearts (50%) and located in the inferior wall in 12. Left ventricle and ventricular septum were involved in 14 (47%) and 6 (20%) cases, respectively. Scattered foci of lymphocytes with myocardial death were observed in 20 cases (67%). Electron microscopy studies, although confirming the myocardial death and lymphocyte infiltrates, did not show any specific ultrastructural substrate. Two pathological patterns, fatty (40%) and fibrofatty (60%), were identified. The fibrofatty pattern was associated with a thinner right ventricular wall ( P P P Conclusions In the fibrofatty variety of ARVC, the myocardial atrophy appears to be the consequence of acquired injury (myocyte death) and repair (fibrofatty replacement), mediated by patchy myocarditis. Whether the inflammation is a primary event or a reaction to spontaneous cell death remains unclear.
267. Familial cardiomyopathy in patients affected by acute myocarditis is strongly associated to DSP gene mutations
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J.M. Serfaty, T. Le Tourneau, F. Kyndt, Nicolas Piriou, Damien Guijarro, V Probst, L. Le Gloan, L Marteau, Karine Warin-Fresse, Claire Toquet, Jean-Baptiste Gourraud, E Conan, Aurélie Thollet, Gilles Lande, and Jean-Noël Trochu
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medicine.medical_specialty ,business.industry ,Cardiomyopathy ,Desmoglein-2 ,Gene mutation ,medicine.disease ,Asymptomatic ,Sudden death ,Right ventricular cardiomyopathy ,Internal medicine ,Cardiology ,Medicine ,cardiovascular diseases ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Index case ,Aunt - Abstract
Introduction The link between acute myocarditis (AM) and familial cardiomyopathies (CM) remains unclear. Purpose To assess the clinical significance of AM in families with CM. Methods We describe the pedigree of 6 families with at least one case of AM and a familial history of CM or sudden death (SD). AM was defined as an infarct-like clinical presentation with normal coronary arteries and myocardial inflammation (MI) documented by cardiac magnetic resonance (CMR), or as an autopsy proven AM. Results In family 1 to 5, genetic testing was triggered by the association of a documented case of AM with an index case of CM or early SD. In this setting, all genetic testing revealed a mutation in the desmoplakin (DSP) gene. In family 1, patient II.1 (15 y.o) was diagnosed with AM 6 months after his 12 y.o sister's SD. In family 2, patient II.4 (17 y.o) was diagnosed with AM. His mother had a DCM, with a CMR revealing the presence of MI. In family 3, patient IV.3 (22 y.o) died suddenly from an AM, attested by post-mortem autopsy. Her aunt had a DCM. In family 4, patient II.4 (41 y.o) had an AM, progressing toward a DCM. Her mother had died suddenly at the age of 39, and her niece had a DCM. In family 5, patient V.16 (9 y.o) presented 4 recurrent episodes of AM. Her cousin's mother had a DCM. In family 6, patient IV.3 had 3 episodes of AM, his father had previously been diagnosed with an arrythmogenic right ventricular cardiomyopathy (ARVC) with a desmoglein 2 (DSG2) mutation ( Table 1 , Fig 1). Conclusion AM is strongly associated to desmosomal mutations when a familial history of cardiomyopathy is present, particularly in DSP gene. In these families, DCM phenotype and SD are frequent, and a notable proportion of isolated LGE suggestive of myocardial fibrosis is present in asymptomatic relatives. These results highlight the need for a comprehensive familial screening in case of AM.
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