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• W2076452380 abstract "HomeCirculation: Cardiovascular GeneticsVol. 7, No. 6Intercalated Discs and Arrhythmogenic Cardiomyopathy Free AccessResearch ArticlePDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBIntercalated Discs and Arrhythmogenic Cardiomyopathy Alessandra Rampazzo, Martina Calore, Jolanda van Hengel and Frans van Roy Alessandra RampazzoAlessandra Rampazzo From the Department of Biology, University of Padua, Padua, Italy (A.R., M.C.); Molecular Cell Biology Unit, Inflammation Research Center (IRC), VIB-Ghent University, Ghent, Belgium (J.v.H., F.v.R.); and Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (J.v.H., F.v.R.). Search for more papers by this author , Martina CaloreMartina Calore From the Department of Biology, University of Padua, Padua, Italy (A.R., M.C.); Molecular Cell Biology Unit, Inflammation Research Center (IRC), VIB-Ghent University, Ghent, Belgium (J.v.H., F.v.R.); and Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (J.v.H., F.v.R.). Search for more papers by this author , Jolanda van HengelJolanda van Hengel From the Department of Biology, University of Padua, Padua, Italy (A.R., M.C.); Molecular Cell Biology Unit, Inflammation Research Center (IRC), VIB-Ghent University, Ghent, Belgium (J.v.H., F.v.R.); and Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (J.v.H., F.v.R.). Search for more papers by this author and Frans van RoyFrans van Roy From the Department of Biology, University of Padua, Padua, Italy (A.R., M.C.); Molecular Cell Biology Unit, Inflammation Research Center (IRC), VIB-Ghent University, Ghent, Belgium (J.v.H., F.v.R.); and Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (J.v.H., F.v.R.). Search for more papers by this author Originally published1 Dec 2014https://doi.org/10.1161/CIRCGENETICS.114.000645Circulation: Cardiovascular Genetics. 2014;7:930–940Heart tissue is subjected to high mechanical stress. Different junctional complexes exist within the intercalated disc (ID) at the site of end-to-end contacts between cardiomyocytes. These junctions are essential for adhesive integrity, morphogenesis, differentiation, and maintenance of cardiac tissue. Recent findings of molecular interactions among intercellular adhesion molecules, gap junctions, and the voltage-gated sodium channel complex suggest that IDs should be considered an organelle in which macromolecular complexes interact specifically to maintain cardiac structure and cardiomyocyte synchrony. It is within this organelle that most of the mutated proteins involved in arrhythmogenic right ventricular cardiomyopathy (ARVC) reside. This inherited cardiomyopathy is characterized by both structural and electric abnormalities of the heart, particularly in young people and athletes. This review highlights recent advances in understanding the link between ID alterations and the molecular genetics and pathogenesis of ARVC.Molecular Complexes at the IDsCardiomyocytes are extensively interconnected at their ends through their IDs, a complex region composed of different kinds of intercellular junctions essential for electric, mechanical, and signaling communication between adjacent cells and, hence, for maintaining correct heart function and growth. Although traditionally depicted as a composition of different separate units, recent data indicate that the ID of cardiomyocytes should be considered a single functional unit in which macromolecular complexes interact mechanically and electrically to maintain cardiomyocyte rigidity and synchrony.Mechanical Junctional ID ComponentsThe ID in vertebrates was originally described as consisting of 3 main junctional complexes: desmosomes, adherens junctions (AJ, also called fascia adherens in cardiac muscle), and gap junctions. It has been proposed that while gap junctions, being essential for chemical and electric coupling of neighboring cells, represent the electric component of ID, desmosomes together with AJ form the mechanical intercellular junctions in cardiomyocytes.1 Desmosomes and AJ are highly specialized anchoring junctions. They are particularly important for maintenance of adhesion and integrity of tissues exposed to mechanical stress and show structures whose blueprints are comparable.2 Both are composed of intercellular adhesion molecules connecting 2 adjacent cardiomyocytes by binding extracellularly like adhesion proteins extending from the adjacent cells; intracellularly, various adaptor proteins involved in signaling or linkage to the cytoskeleton.3In the cardiac desmosome, desmoglein-2 and desmocollin-2, both transmembrane proteins of the cadherin family, mediate intercellular adhesion, and through their cytoplasmic domains, they serve as a scaffold for assembly of the desmosomal plaque (Figure 1). Indeed, these cytoplasmic domains provide a binding platform for the armadillo family members plakoglobin and plakophilin-2, which in turn associate with desmoplakin isoforms, which complete the link with desmin intermediate filaments (IF) through their C termini. This interaction of IF with desmosomes propagates the tensile strength imparted by the IF cytoskeleton across the entire tissue and is essential for myocardium integrity.4,5 In the heart, AJ-like junctions consist of homodimers of N-cadherin, a classical cadherin that mediates intercellular adhesion through its extracellular domain, whereas its cytoplasmic tail is linked to so-called catenins of the armadillo protein family: p120ctn, β-catenin, and plakoglobin (Figure 1). The junctional role of β-catenin has been well studied particularly in epithelial cells: through interaction with αE-catenin, β-catenin forms a direct or indirect link with the F-actin cytoskeleton.Download figureDownload PowerPointFigure 1. Molecular composition of the intercalated disc (ID) connecting cardiomyocytes. The various proteins are identified in the box on the right. Besides the ion channels, in particular, the cardiac sodium channel, 3 types of junctional complexes exist. Classical gap junctions are composed of connexins, mainly connexin-43 (Cx43) in the heart. Classical desmosomes are composed of desmosomal cadherins, which make intercellular connections and are connected via the armadillo proteins plakoglobin and plakophilin-2 to desmoplakin, which in turn recruits intermediate filaments of the desmin type. The third junction is the heart-specific area composita (AC), also called mixed-type adherens junction. A hallmark of the AC is the amalgamation of proteins typical of genuine desmosomes and of genuine adherens junctions (AJ), the latter being best studied in epithelial cells. Thus, in cardiac AC N-cadherin is extracellularly connected via β-catenin (or plakoglobin) to α-catenin, which in turn binds via vinculin to the F-actin cytoskeleton. However, in the heart, 2 forms of α-catenin are expressed: αE-catenin (which is widely expressed) and αT-catenin (which is enriched in the heart). αT-catenin has the unique capacity to bind also plakophilin-2, and this interaction is thought to be fundamental for the generation and stability of the AC. The relatively large size of the AC, and its combined linkage to both F-actin and intermediate filaments, is expected to provide the strong intercellular linkages necessary to support the mechanical stresses in heart tissue. As discussed in the text, arrhythmogenic right ventricular cardiomyopathy (ARVC) can be caused by mutations in many of the proteins depicted here, often in plakophilin-2 but also in αT-catenin. Moreover, the cross talk between the various molecular complexes shown here can be drastically distorted by the disease. Therefore, ARVC may be considered a disease of the ID, rather than a purely desmosomal disease.Accessory proteins, such as vinculin and EPLIN, are also involved in AJ. Together with αE-catenin, they confer mechanosensitive properties to these junctions.6,7 It is unclear whether all those molecular interactions occur also in cardiomyocytes, but recent evidence suggests that also here AJ proteins are involved in mechanotransduction, the process of converting mechanical stimuli into biochemical signals and cytoskeletal remodeling. The cadherin–catenin complex seems to constitute an attachment site for myofibrils spanning adjacent cells and is thus essential for myofibril continuity across sarcolemma.8,9 In particular, a direct role has been demonstrated for N-cadherin, not only in intercellular adhesion but also in bidirectional transmission of cytoskeletal tension between contractile cells.10,11 In individual neonatal rat cardiomyocytes cultured on N-cadherin–coated Y-shaped micropatterns, αE-catenin localized to areas of high internal stress, but this was not the case when fibronectin-coated micropatterns were used.12 This focal enrichment was disturbed when a myosin ATPase inhibitor was used. From these and similar experiments, it was concluded that the N-cadherin/αE-catenin complex regulates sarcomeric organization according to the mechanical stimulus and does so differently from integrin/vinculin complexes.Area Composita: A Peculiar Junction at the IDInterestingly, in vivo studies demonstrated that only in nonmammalian vertebrates and during fetal stages of mammalian development, AJ and desmosomes become uniformly distributed throughout the sarcolemma.13,14 However, mammalian heart development continues postnatally with the polar clustering and amalgamation of AJ and desmosomal proteins into the ID.14–16 By postnatal day 90, in mice, these junctional proteins are no longer restricted to distinct structures but exist almost completely in a hybrid and enforced structure, that is linked to both the actin cytoskeleton and the desmin IF.16 Similar observations were made for cardiac IDs of other mammals, including man.15–17 This ID-specific hybrid junction has been termed area composita (AC) (Figure 1).14,15,17,18 Indeed, immunofluorescence and immunoelectron microscopy performed on myocardial samples of several mammalian species revealed in the AC the colocalization of different junctional proteins in more promiscuous assemblies than originally thought.15,17 Apparently, in the same molecular complex, genuine desmosomal proteins, such as desmoplakin, the desmosomal cadherins, plakoglobin, and plakophilin-2, were observed in addition to N-cadherin, β-catenin, αE- and αT-catenins, p120ctn, myozap, and vinculin, all of which are components thought to be typical of cardiac AJ. The special mix of 2 major junctional ensembles and the resulting hybrid character of the AC are also underlined by the specific interaction in the myocardium of the desmosomal protein plakophilin-2 with αT-catenin, which shows high homology with αE-catenin.19 The αE-catenin is a typical component of the AJ plaque, but it cannot bind plakophilin-2. Thus, the occurrence of a peculiar AC instead of an AJ at the ID could be a means of modulating and strengthening cell–cell adhesion between cardiac muscle cells.In this novel view of the ID, most mechanical junctions at the ID appear as an extended, sometimes continuous system composed mainly of desmosomal proteins and AJ proteins intimately associated with each other. This AC occupies >90% of the ID area and is interrupted only by few gap junctions, genuine desmosomes, and rather small junction-free regions.17 Junctions with desmosomal morphology occupy only a relatively minor proportion of the ID, often only ≤15%.15,18Interestingly, the AC is not found in hearts of lower vertebrates, such as amphibian or fish species, in which desmosomes and AJ remain separate ensembles.20 In avian hearts, only a small fraction of desmosomal proteins appear as AC. This suggests that the AC might have evolved to support the increased mechanical load on the mammalian heart because it anchors at the ID both actin and IF cytoskeletons over an extended junctional area.20,21 Taken together, these data indicate the importance of the AC in maintenance of the shape and the adhesion properties of cardiomyocytes in mammals, and thus in cardiac function in general.Complex Links of the ID to the CytoskeletonIn view of the essential role of the ID in intercellular adhesion and mechanical transduction, the binding of its various components to cytoskeletal elements and its functional implications should be scrutinized. As mentioned above, there is mounting evidence that α-catenins are more than linker molecules. In the AC of cardiomyocytes, 2 isoforms of α-catenins are expressed: αE- and αT-catenin.19,22 At least for αE-catenin, it has been reported that it functions as a dynamic cytoskeleton modulator with tension-dependent junctional effects and nonjunctional effects.6,7 Homodimeric forms of αE-catenin can inhibit Arp2/3-dependent actin polymerization, thereby preventing the formation of branched F-actin.23,24 However, in epithelial cells, junctional αE-catenin can interact either with formin-1, leading to nucleation of unbranched actin filaments25,26 or with EPLIN. This contributes to the assembly of mechanoresistant AJ.27 One may wonder whether F-actin–modulating proteins with analogy to formin-1 or EPLIN are expressed in the myocardium, and if so, whether they show any specific interaction with one or both types of α-catenin at the ID. Moreover, the binding of αE-catenin, and possibly also αT-catenin, to the actin-binding proteins α-actinin and vinculin may also be important for local F-actin organization at the ID.6,7 α-actinin is a component of cardiac Z-discs and might bind to α-catenins in the so-called cardiac transitional junction.28 The latter region seems to link physically the highly ordered sarcomeric structures of the cardiomyocyte to the AC in the ID. Zygotic knockout of vinculin results in prenatal death as a result of severe defects in brain and heart.29 It is also noteworthy that the heart expresses the formin family member Daam1, and abrogation of Daam1 by gene-trap technology was reported to cause multiple defects in the cytoskeletal architecture of the heart, including perturbation of the AC.30Cross talk of Mechanical Junctions With Gap Junctions and Voltage-Gated Sodium ChannelsThe ID is composed of discrete molecular complexes (desmosomes, areae compositae, and gap junctions). Nonetheless, in recent years, several reports demonstrated that these structures belong to a communal network, the components of which interact synergistically at the cell–cell contacts. Molecules conventionally defined as belonging to 1 complex are also relevant to the function of the others.It has been demonstrated that the mechanical junction protein plakophilin-2 and the gap-junction protein connexin-43 (Cx43) coexist in the same macromolecular complex because plakophilin-2 clusters have been found within the boundaries of the Cx43 plaque.31,32 The relationship between these 2 molecules seems to extend to the functional level because shRNA-mediated knockdown of plakophilin-2 expression in rat ventricular cardiomyocytes led to a reduction in Cx43 amounts at intercellular contacts together with a decreased dye coupling between the cells.31 This indicates that plakophilin-2 directly modulates Cx43. On the contrary, Cx43 has been demonstrated to be relevant to mechanical coupling, as shown by an elegant dispase assay performed in HEK293 cells by the group of Delmar.33 However, whether this finding involves a physical interaction between Cx43 and mechanical junction proteins, or whether it is a consequence of intercellular adhesion mediated by gap junctions, remains to be determined.Interactions at the ID have also been observed between mechanical junction proteins and several nonjunctional molecules. Sato et al34,35 demonstrated that the voltage-gated sodium channel (NaV1.5) and ankyrin-G (AnkG), a scaffolding protein for the sodium channel, are involved in the binding and functional interaction with mechanical junction proteins. Indeed, NaV1.5 was found to coimmunoprecipitate with Cx43, N-cadherin, and plakophilin-2 and to coexist in apparently the same molecular complex at rat cardiac ID.34 Furthermore, in neonatal rat cardiomyocytes with plakophilin-2 knockdown, the sodium current (INa) significantly decreased, and optical mapping experiments demonstrated increased re-entrant activity and significantly decreased conduction velocity when compared with control cardiomyocytes.34 More recently, the authors demonstrated that knockdown of AnkG expression in neonatal rat cardiomyocytes led to significant changes in subcellular distribution and abundance of Cx43 and plakophilin-2, as well as a reduction in intercellular adhesion strength and electric coupling.35 Reciprocal regulation of the abundance of AnkG and the localization of NaV1.5 by plakophilin-2 have also been demonstrated.35 However, the precise contribution of AnkG to the overall adhesion strength of cardiomyocytes in situ is still unknown. Other groups, who used HL-1 cells or induced pluripotent stem cell (iPSC)–derived cardiomyocytes from a patient with plakophilin-2 deficiency, reported a correlation between plakophilin-2 deficiency and the reduction of INa amplitude, even in the absence of compromised cardiac structural integrity.36,37 Similar results correlating mechanical junction protein abnormalities with reduction in INa amplitude have been observed also in vivo, both in mouse models with Pkp2 haploinsufficiency or with cardiac overexpression of a mutated desmoglein-2, and in humans carrying desmoplakin mutations.38–40Taken together, these data indicate that proteins of different intercellular structures are more closely linked than originally thought. This implies a more complex picture of the ID as a connexome, a molecular interaction network in which proteins of different junctional and nonjunctional complexes can regulate the functions of others, and together, control cardiac excitability, electric coupling, and intercellular adhesion.41Changes in IDs Lead to ARVCARVC is a primary inherited myocardial disorder characterized by progressive cardiomyocyte death, followed by fatty or fibrofatty replacement.42,43 ARVC is nowadays one of the leading causes of sudden cardiac death in young people and athletes and accounts for up to 10% of deaths from undiagnosed cardiac disease in people aged ≤65 years.44 ARVC is usually diagnosed at the age of 20 to 40 years. Patients are seldom ≤10 years although sporadic cases have been observed early in life, and even in the embryological phase, when the high dosage of some drugs may potentially contribute to its development.45,46 ARVC prevalence is estimated at between 1:2000 and 1:5000,47 and it affects men more frequently than women, with a 2.4:1 ratio.48The most typical clinical presentation has 2 aspects: (1) electrocardiographic abnormalities, such as ventricular tachycardia with left bundle branch morphology, and T-wave inversion in the V1 to V3 leads and (2) functional and structural abnormalities mostly of the right ventricle, such as wall thinning, regional wall motion alterations, and global dilation. The disease is clinically heterogeneous, with interfamilial and intrafamilial variability, and its morbidity ranges from benign to malignant forms.42,44 The broad phenotypic spectrum encompasses the right form as well as left-dominant and biventricular subtypes, and adoption of the more comprehensive term arrhythmogenic cardiomyopathy might be appropriate.47Development of ARVC and its associated arrhythmic risk turned out to be influenced by exercise, which increases the risk of sudden cardiac death by 5-fold.47 Recently, the first systematic human study on endurance athletes carrying ARVC causing mutations reported an association between exercise per year, clinical diagnosis, ventricular arrhythmias, and heart failure.49 Furthermore, reducing exercise duration reduced arrhythmic risk and altered the clinical course of the disease.Molecular Genetics of ARVCSystematic evaluation of first- and second-degree relatives of affected probands suggests that up to 50% of ARVC cases are familial and follow an autosomal-dominant pattern of inheritance with incomplete penetrance and variable phenotypic expression.43 The majority of disease-causing mutations detected in patients with ARVC occurs in genes encoding desmosomal and AC proteins (Table 1). 56,62 For the genes mentioned below, heterozygous mutations are commonly detected in patients with ARVC but homozygous mutations are rare. 74Table 1. Human Genes Associated With ARVCGeneChromosome LocusProteinCellular LocalizationARVC Mutation PrevalencePhenotypeReferencesMechanical junctional ARVC genes JUP17q21Junction plakoglobinDesmosome/area compositaRareARVC, Naxos disease, DCM50–52 DSP6p24DesmoplakinDesmosome/area composita6%–16%ARVC, Carvajal disease, DCM53–56 PKP212p11Plakophilin-2Desmosome/area composita7%–70%ARVC, DCM,Brugada syndrome37,55–57 DSG218q12Desmoglein-2Desmosome/area composita5%–25%ARVC, DCM56,58 DSC218q12Desmocollin-2Desmosome/area compositaRareARVC, DCM56,59–61 CTNNA310q21αT-cateninArea compositaRareARVC62Other known ARVC genes RYR21q42-q43Ryanodine receptor 2Sarcoplasmic reticulumRareARVC, CPVT63 TGFB314q23-q24Transforming growth factor β3SecretedRareARVC64,65 TMEM433p25Transmembrane protein 43 (TMEM43; LUMA)Nuclear envelopeRareARVC66,67 DES2q35DesminIntermediate filamentsRareOverlap syndrome68–70 TTN2q31TitinSarcomereRareOverlap syndrome71 LMNA1q21.2-q21.3Lamin A/CNuclear envelopeRareOverlap syndrome72 PLN6q22.1PhospholambanSarcoplasmic reticulumRareARVC, DCM, overlap syndrome73ARVC indicates arrhythmogenic right ventricular cardiomyopathy; CPVT, catecholaminergic polymorphic ventricular tachycardia; and DCM, dilated cardiomyopathy.The first ARVC locus was mapped in 1994, at 14q23-q24, after evaluation of a large Venetian family.75 It was only in 2000 that the first causal gene for an ARVC-associated recessive disorder, Naxos syndrome, was identified. This disease is characterized by palmoplantar keratoderma, woolly hair, and ARVC, and it is caused by a recessive mutation in the JUP gene, encoding plakoglobin.50 A dominant mutation in JUP was detected in an ARVC family without cutaneous abnormalities and was found to affect plakoglobin stability at the junctions.51 Genome-wide linkage analysis of a large Italian family showed for the first time that the desmoplakin gene (DSP) is the cause of the classic autosomal dominant ARVC form.53 Many other homozygous and mostly heterozygous mutations in DSP have been detected in patients showing ARVC, and they were rarely combined with cutaneous abnormalities.54,56Because plakoglobin and desmoplakin were known to be key proteins of desmosomes,5 the focus of the gene hunt in ARVC was directed to genes encoding other desmosomal proteins. PKP2, encoding plakophilin-2, is the most commonly mutated gene among patients with ARVC, with an estimated prevalence ranging from 7% to 51% and spikes of 70% (Table 1).56,57 The varying mutation prevalence of PKP2 gene in different cohorts might be because of the presence of founder mutations, the strictness with which diagnostic criteria are applied, the use of inconsistent definitions for pathogenicity, and geographical variations in genetic and nongenetic factors. Recently, different research groups detected in ARVC families heterozygous deletions of some PKP2 exons and even of the entire PKP2 gene, recurring with a frequency of 2%.56,76–78On the basis of its mutation rate, the desmoglein-2 gene (DSG2), together with DSP and PKP2, belongs to the so-called 3 big ARVC genes. Heterozygous mutations in DSG2 have been identified in patients with ARVC with a frequency range of 5% to 25% in different cohorts.56,58 Pathogenic mutations were originally found in the desmocollin-2 gene (DSC2) by Syrris et al.59 Later, only a few more mutations in this gene have been detected.56,60,61In different cohorts, a significant proportion (4%−11%) of the patients were found to carry >1 mutation in the same or in different ARVC genes.57,79–81 Compared with patients with a single ARVC mutation, carriers of multiple mutations exhibited more severe disease manifestations, such as higher prevalence of left ventricular involvement, major right ventricular dilatation, increased risk of lifetime major arrhythmic events, VT and syncope, or more frequent personal history of sudden cardiac death (aborted or not).57,79,82,83Although the majority of ARVC mutations occurs in genes encoding ID proteins, few ARVC mutations have been detected in genes unrelated to intercellular junction complexes, such as RYR2 (ryanodine receptor 2),63TGFΒ3 (transforming growth factor β 3),64,65TMEM43 (encoding the protein previously known as LUMA),66DES (desmin),68–70TTN (titin),71LMNA (lamin A/C),72 and PLN (phospholamban).73,84 Mutations in the RYR2 gene have been shown to account for an atypical form of ARVC associated with polymorphic ventricular arrhythmias and for catecholaminergic polymorphic ventricular tachycardia, a peculiar malignant arrhythmic disease.85 Most probably, the 2 diseases belong to the same nosographic entity.Recently, using the candidate gene approach, our group identified CTNNA3 as a novel ARVC gene.62 This gene encodes αT-catenin, which binds plakophilin-2 and thereby contributes to the formation of the AC.19,22 On the basis of the most recent description of the ID organization and the identification of this novel ARVC gene, we propose that ARVC may be considered a disease of the ID, rather than a purely desmosomal disease (Figure 2; Table 1).Download figureDownload PowerPointFigure 2. Scheme of junctional structures in (A) normal intercalated discs (IDs) of adult mammalian heart and in (B) arrhythmogenic right ventricular cardiomyopathy (ARVC) pathological heart caused by mutations in ID components. A, Typical composition of ID-associated junctions in healthy heart. Depicted are desmosomes (green), areae compositae (red), and gap junctions (blue). Black lines: cardiac sarcolemma; dark green filaments: desmin-containing intermediate filaments; light orange filaments: actin-rich myofilaments; dark orange filaments: myosin-rich myofilaments. B, IDs of ARVC heart in patients with mutations in genes encoding area composita or desmosomal proteins, which are expected to affect all 3 intercellular junction types. Remodeling of cardiac gap junctions and pale areas lacking filaments adjacent to the IDs are frequently observed in ARVC-afflicted hearts.86–88 The negative effect on each of the 3 intercellular junction types at the IDs results in ARVC pathology. Modified after Pieperhoff et al.18Comprehensive mutation screening of known ARVC genes can detect causative mutations in ≈50% of probands,44 suggesting that additional genes could be involved in the genetic determination of the disease. Several candidate genes encoding proteins related to cell–cell junctions were screened for mutations (Table 2), but negative results were obtained.89–91 However, these studies were performed on a small number of patients with ARVC, suggesting the need to assess all these genes in large cohorts. Future research on ARVC genes should be focused on other components of cardiomyocyte adhesion, such as ARVCF and p120ctn,18 as well as into components of pathways involved in ID junction assembly. Rho-family GTPases have a well-established and important role in E-cadherin–mediated cell–cell adhesion.92 In skin keratinocytes, the Rho/Rho-kinase pathway has been shown to be necessary for normal desmosomal assembly.93 Moreover, recent studies in keratinocytes demonstrated a cross talk between the Rho/Rho-kinase pathway and plakophilin-2 and plakoglobin.94,95 These findings suggest that the Rho/Rho-kinase pathway might be equally important for assembly or stability of the cardiac ID although that has not been reported yet. Recently, a novel protein expressed at high levels in the heart, myozap, was identified as a component of the cytoplasmic plaques of the AC in the myocardial ID.96 Interestingly, myozap can interact with desmoplakin, ZO-1, and dysbindin. The latter is also strongly expressed in the heart and is an interaction partner of RhoA,97 whereas myozap interacts with myosin phosphatase-RhoA interacting protein, a negative regulator of Rho activity.96 Both myozap and dysbindin contribute in a RhoA-dependent way to activation of the transcription factor SRF (serum response factor). Myozap inhibition in zebrafish, as well as overexpression of dysbindin in cultured rat cardiomyocytes and cardiac-restricted overexpression of myozap in transgenic mice, induces various forms of cardiomyopathy but no ARVC-like phenotype.96–98Table 2. Candidate Genes Screened for Mutations in ARVC ProbandsGeneChromosome LocusProteinCellular LocalizationNo. of ARVC Probands ScreenedReferencesPKP42q24.1Plakophilin-4Desmosome6489CTNNB13p21Beta-cateninArea composita6590MYL33p21.31Myosin light chain 3Sarcomere1491CTNNA15q31.2AlphaE-cateninArea composita1491GJA16q22.31Connexin 43Gap junction1491PERP6q24PerpDesmosome64, 6589, 90CAV17q31Caveolin-1Caveolae6489MVCL10q22.2MetavinculinContractile apparatus1491MYL212q24.11Myosin light chain 2Sarcomere1491PNN14q21.1PininDesmosome associated6489ACTC115q14Actin alpha cardiac muscle 1Sarcomere1491CDH218q12.1N-cadherinArea composita1491Genetic screening has been assuming an important role in clinical evaluation. It allows interpretation of borderline clinical phenotypes and early identification of asymptomatic carriers. Genetic testing is especially useful in families with ≥1 affected member who carries a pathogenic mutation because it allows presymptomatic diagnosis among relatives. Symptom-free carriers need lifelong clinical assessment, because the disease is progressive and can appear late in life. Restriction of physical e" @default.
• W2076452380 created "2016-06-24" @default.
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• W2076452380 date "2014-12-01" @default.
• W2076452380 modified "2023-10-14" @default.
• W2076452380 title "Intercalated Discs and Arrhythmogenic Cardiomyopathy" @default.
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