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Vanaja IP, Scalco A, Ronfini M, Bona AD, Olianti C, Rizzo S, Chelko SP, Corrado D, Sacconi L, Basso C, Mongillo M, Zaglia T. Cardiac sympathetic neurons are additional cells affected in genetically determined arrhythmogenic cardiomyopathy. J Physiol 2025; 603:1959-1982. [PMID: 39141822 PMCID: PMC11955870 DOI: 10.1113/jp286845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 07/05/2024] [Indexed: 08/16/2024] Open
Abstract
Arrhythmogenic cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes, which accounts for most cases of stress-related arrhythmic sudden death, in young and athletes. AC hearts display fibro-fatty lesions that generate the arrhythmic substrate and cause contractile dysfunction. A correlation between physical/emotional stresses and arrhythmias supports the involvement of sympathetic neurons (SNs) in the disease, but this has not been confirmed previously. Here, we combined molecular, in vitro and ex vivo analyses to determine the role of AC-linked DSG2 downregulation on SN biology and assess cardiac sympathetic innervation in desmoglein-2 mutant (Dsg2mut/mut) mice. Molecular assays showed that SNs express DSG2, implying that DSG2-mutation carriers would harbour the mutant protein in SNs. Confocal immunofluorescence of heart sections and 3-D reconstruction of SN network in clarified heart blocks revealed significant changes in the physiologialc SN topology, with massive hyperinnervation of the intact subepicardial layers and heterogeneous distribution of neurons in fibrotic areas. Cardiac SNs isolated from Dsg2mut/mut neonatal mice, prior to the establishment of cardiac innervation, show alterations in axonal sprouting, process development and distribution of varicosities. Consistently, virus-assisted DSG2 downregulation replicated, in PC12-derived SNs, the phenotypic alterations displayed by Dsg2mut/mut primary neurons, corroborating that AC-linked Dsg2 variants may affect SNs. Our results reveal that altered sympathetic innervation is an unrecognized feature of AC hearts, which may result from the combination of cell-autonomous and context-dependent factors implicated in myocardial remodelling. Our results favour the concept that AC is a disease of multiple cell types also hitting cardiac SNs. KEY POINTS: Arrhythmogenic cardiomyopathy is a genetically determined cardiac disease, which accounts for most cases of stress-related arrhythmic sudden death. Arrhythmogenic cardiomyopathy linked to mutations in desmoglein-2 (DSG2) is frequent and leads to a left-dominant form of the disease. Arrhythmogenic cardiomyopathy has been approached thus far as a disease of cardiomyocytes, but we here unveil that DSG2 is expressed, in addition to cardiomyocytes, by cardiac and extracardiac sympathetic neurons, although not organized into desmosomes. AC-linked DSG2 downregulation primarily affect sympathetic neurons, resulting in the significant increase in cardiac innervation density, accompanied by alterations in sympathetic neuron distribution. Our data supports the notion that AC develops with the contribution of several 'desmosomal protein-carrying' cell types and systems.
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Affiliation(s)
- Induja Perumal Vanaja
- Department of Cardiac, Thoracic, Vascular Sciences and Public HealthUniversity of PadovaPadovaItaly
- Veneto Institute of Molecular Medicine (VIMM)PadovaItaly
| | - Arianna Scalco
- Veneto Institute of Molecular Medicine (VIMM)PadovaItaly
- Department of Biomedical SciencesUniversity of PadovaPadovaItaly
| | - Marco Ronfini
- Veneto Institute of Molecular Medicine (VIMM)PadovaItaly
- Department of Biomedical SciencesUniversity of PadovaPadovaItaly
| | - Anna Di Bona
- Department of Cardiac, Thoracic, Vascular Sciences and Public HealthUniversity of PadovaPadovaItaly
- Veneto Institute of Molecular Medicine (VIMM)PadovaItaly
| | - Camilla Olianti
- Institute of Clinical Physiology (IFC)National Research CouncilFlorenceFlorenceItaly
| | - Stefania Rizzo
- Department of Cardiac, Thoracic, Vascular Sciences and Public HealthUniversity of PadovaPadovaItaly
| | - Stephen P. Chelko
- Department of MedicineJohns Hopkins University, School of MedicineBaltimoreMDUSA
- Department of Biomedical SciencesFlorida State University, College of MedicineTallahasseeFLUSA
| | - Domenico Corrado
- Department of Cardiac, Thoracic, Vascular Sciences and Public HealthUniversity of PadovaPadovaItaly
| | - Leonardo Sacconi
- Institute of Clinical Physiology (IFC)National Research CouncilFlorenceFlorenceItaly
- Institute for Experimental Cardiovascular MedicineUniversity Heart Center and Medical Faculty, University of FreiburgFreiburgGermany
| | - Cristina Basso
- Department of Cardiac, Thoracic, Vascular Sciences and Public HealthUniversity of PadovaPadovaItaly
| | - Marco Mongillo
- Veneto Institute of Molecular Medicine (VIMM)PadovaItaly
- Department of Biomedical SciencesUniversity of PadovaPadovaItaly
| | - Tania Zaglia
- Veneto Institute of Molecular Medicine (VIMM)PadovaItaly
- Department of Biomedical SciencesUniversity of PadovaPadovaItaly
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2
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Vencato S, Romanato C, Rampazzo A, Calore M. Animal Models and Molecular Pathogenesis of Arrhythmogenic Cardiomyopathy Associated with Pathogenic Variants in Intercalated Disc Genes. Int J Mol Sci 2024; 25:6208. [PMID: 38892395 PMCID: PMC11172742 DOI: 10.3390/ijms25116208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/28/2024] [Accepted: 06/01/2024] [Indexed: 06/21/2024] Open
Abstract
Arrhythmogenic cardiomyopathy (ACM) is a rare genetic cardiac disease characterized by the progressive substitution of myocardium with fibro-fatty tissue. Clinically, ACM shows wide variability among patients; symptoms can include syncope and ventricular tachycardia but also sudden death, with the latter often being its sole manifestation. Approximately half of ACM patients have been found with variations in one or more genes encoding cardiac intercalated discs proteins; the most involved genes are plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmoplakin (DSP). Cardiac intercalated discs provide mechanical and electro-metabolic coupling among cardiomyocytes. Mechanical communication is guaranteed by the interaction of proteins of desmosomes and adheren junctions in the so-called area composita, whereas electro-metabolic coupling between adjacent cardiac cells depends on gap junctions. Although ACM has been first described almost thirty years ago, the pathogenic mechanism(s) leading to its development are still only partially known. Several studies with different animal models point to the involvement of the Wnt/β-catenin signaling in combination with the Hippo pathway. Here, we present an overview about the existing murine models of ACM harboring variants in intercalated disc components with a particular focus on the underlying pathogenic mechanisms. Prospectively, mechanistic insights into the disease pathogenesis will lead to the development of effective targeted therapies for ACM.
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Affiliation(s)
- Sara Vencato
- Department of Biology, University of Padova, Via U. Bassi 58/B, 35121 Padova, Italy; (S.V.); (C.R.); (A.R.)
| | - Chiara Romanato
- Department of Biology, University of Padova, Via U. Bassi 58/B, 35121 Padova, Italy; (S.V.); (C.R.); (A.R.)
| | - Alessandra Rampazzo
- Department of Biology, University of Padova, Via U. Bassi 58/B, 35121 Padova, Italy; (S.V.); (C.R.); (A.R.)
| | - Martina Calore
- Department of Biology, University of Padova, Via U. Bassi 58/B, 35121 Padova, Italy; (S.V.); (C.R.); (A.R.)
- Department of Molecular Genetics, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6211 LK Maastricht, The Netherlands
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Kyriakopoulou E, Versteeg D, de Ruiter H, Perini I, Seibertz F, Döring Y, Zentilin L, Tsui H, van Kampen SJ, Tiburcy M, Meyer T, Voigt N, Tintelen VJP, Zimmermann WH, Giacca M, van Rooij E. Therapeutic efficacy of AAV-mediated restoration of PKP2 in arrhythmogenic cardiomyopathy. NATURE CARDIOVASCULAR RESEARCH 2023; 2:1262-1276. [PMID: 38665939 PMCID: PMC11041734 DOI: 10.1038/s44161-023-00378-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 10/27/2023] [Indexed: 04/28/2024]
Abstract
Arrhythmogenic cardiomyopathy is a severe cardiac disorder characterized by lethal arrhythmias and sudden cardiac death, with currently no effective treatment. Plakophilin 2 (PKP2) is the most frequently affected gene. Here we show that adeno-associated virus (AAV)-mediated delivery of PKP2 in PKP2c.2013delC/WT induced pluripotent stem cell-derived cardiomyocytes restored not only cardiac PKP2 levels but also the levels of other junctional proteins, found to be decreased in response to the mutation. PKP2 restoration improved sodium conduction, indicating rescue of the arrhythmic substrate in PKP2 mutant induced pluripotent stem cell-derived cardiomyocytes. Additionally, it enhanced contractile function and normalized contraction kinetics in PKP2 mutant engineered human myocardium. Recovery of desmosomal integrity and cardiac function was corroborated in vivo, by treating heterozygous Pkp2c.1755delA knock-in mice. Long-term treatment with AAV9-PKP2 prevented cardiac dysfunction in 12-month-old Pkp2c.1755delA/WT mice, without affecting wild-type mice. These findings encourage clinical exploration of PKP2 gene therapy for patients with PKP2 haploinsufficiency.
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Affiliation(s)
- Eirini Kyriakopoulou
- Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands
| | - Danielle Versteeg
- Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands
| | - Hesther de Ruiter
- Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands
| | - Ilaria Perini
- Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands
| | - Fitzwilliam Seibertz
- Institute of Pharmacology and Toxicology, University Medical Center Gottingen (UMG), Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany
- Cluster of Excellence ‘Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells’ (MBExC), University of Göttingen, Göttingen, Germany
- Nanion Technologies GmbH, Munich, Germany
| | - Yannic Döring
- Institute of Pharmacology and Toxicology, University Medical Center Gottingen (UMG), Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany
| | - Lorena Zentilin
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Hoyee Tsui
- Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands
| | | | - Malte Tiburcy
- Institute of Pharmacology and Toxicology, University Medical Center Gottingen (UMG), Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany
| | - Tim Meyer
- Institute of Pharmacology and Toxicology, University Medical Center Gottingen (UMG), Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany
| | - Niels Voigt
- Institute of Pharmacology and Toxicology, University Medical Center Gottingen (UMG), Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany
- Cluster of Excellence ‘Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells’ (MBExC), University of Göttingen, Göttingen, Germany
| | | | - Wolfram H. Zimmermann
- Institute of Pharmacology and Toxicology, University Medical Center Gottingen (UMG), Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany
- Cluster of Excellence ‘Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells’ (MBExC), University of Göttingen, Göttingen, Germany
- German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Göttingen, Germany
| | - Mauro Giacca
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, King’s College London, London, UK
| | - Eva van Rooij
- Hubrecht Institute-KNAW and Utrecht University Medical Center, Utrecht, the Netherlands
- Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
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Bradford WH, Zhang J, Gutierrez-Lara EJ, Liang Y, Do A, Wang TM, Nguyen L, Mataraarachchi N, Wang J, Gu Y, McCulloch A, Peterson KL, Sheikh F. Plakophilin 2 gene therapy prevents and rescues arrhythmogenic right ventricular cardiomyopathy in a mouse model harboring patient genetics. NATURE CARDIOVASCULAR RESEARCH 2023; 2:1246-1261. [PMID: 39196150 PMCID: PMC11357983 DOI: 10.1038/s44161-023-00370-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 10/16/2023] [Indexed: 08/29/2024]
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a fatal genetic heart disease characterized by cardiac arrhythmias, in which fibrofatty deposition leads to heart failure, with no effective treatments. Plakophilin 2 (PKP2) is the most frequently mutated gene in ARVC, and although altered RNA splicing has been implicated, there are no models to study its effect and therapeutics. Here, we generate a mouse model harboring a PKP2 mutation (IVS10-1G>C) affecting RNA splicing, recapitulating ARVC features and sudden death starting at 4 weeks. Administering AAV-PKP2 gene therapy (adeno-associated viral therapy to drive cardiac expression of PKP2) to neonatal mice restored PKP2 protein levels, completely preventing cardiac desmosomal and pathological deficits associated with ARVC, ensuring 100% survival of mice up to 6 months. Late-stage AAV-PKP2 administration rescued desmosomal protein deficits and reduced pathological deficits including improved cardiac function in adult mice, resulting in 100% survival up to 4 months. We suggest that AAV-PKP2 gene therapy holds promise for circumventing ARVC associated with PKP2 mutations, including splice site mutations.
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Affiliation(s)
- William H Bradford
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Jing Zhang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | | | - Yan Liang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Aryanne Do
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Tsui-Min Wang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Lena Nguyen
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | | | - Jie Wang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Yusu Gu
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Andrew McCulloch
- Department of Bioengineering, University of California San Diego, La Jolla, CA, USA
| | - Kirk L Peterson
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Farah Sheikh
- Department of Medicine, University of California San Diego, La Jolla, CA, USA.
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5
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Bos TA, Piers SRD, Wessels MW, Houweling AC, Bökenkamp R, Bootsma M, Bosman LP, Evertz R, Hellebrekers DMEI, Hoedemaekers YM, Knijnenburg J, Lekanne Deprez R, van Mil AM, Te Riele ASJM, van Slegtenhorst MA, Wilde AAM, Yap SC, Dooijes D, Koopmann TT, van Tintelen JP, Barge-Schaapveld DQCM. The arrhythmogenic cardiomyopathy phenotype associated with PKP2 c.1211dup variant. Neth Heart J 2023:10.1007/s12471-023-01791-2. [PMID: 37505369 PMCID: PMC10400759 DOI: 10.1007/s12471-023-01791-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2023] [Indexed: 07/29/2023] Open
Abstract
BACKGROUND The arrhythmogenic cardiomyopathy (ACM) phenotype, with life-threatening ventricular arrhythmias and heart failure, varies according to genetic aetiology. We aimed to characterise the phenotype associated with the variant c.1211dup (p.Val406Serfs*4) in the plakophilin‑2 gene (PKP2) and compare it with previously reported Dutch PKP2 founder variants. METHODS Clinical data were collected retrospectively from medical records of 106 PKP2 c.1211dup heterozygous carriers. Using data from the Netherlands ACM Registry, c.1211dup was compared with 3 other truncating PKP2 variants (c.235C > T (p.Arg79*), c.397C > T (p.Gln133*) and c.2489+1G > A (p.?)). RESULTS Of the 106 carriers, 47 (44%) were diagnosed with ACM, at a mean age of 41 years. By the end of follow-up, 29 (27%) had experienced sustained ventricular arrhythmias and 12 (11%) had developed heart failure, with male carriers showing significantly higher risks than females on these endpoints (p < 0.05). Based on available cardiac magnetic resonance imaging and echocardiographic data, 46% of the carriers showed either right ventricular dilatation and/or dysfunction, whereas a substantial minority (37%) had some form of left ventricular involvement. Both geographical distribution of carriers and haplotype analysis suggested PKP2 c.1211dup to be a founder variant originating from the South-Western coast of the Netherlands. Finally, a Cox proportional hazards model suggested significant differences in ventricular arrhythmia-free survival between 4 PKP2 founder variants, including c.1211dup. CONCLUSIONS The PKP2 c.1211dup variant is a Dutch founder variant associated with a typical right-dominant ACM phenotype, but also left ventricular involvement, and a possibly more severe phenotype than other Dutch PKP2 founder variants.
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Affiliation(s)
- Thomas A Bos
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Sebastiaan R D Piers
- Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Marja W Wessels
- Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Arjan C Houweling
- Department of Human Genetics, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Regina Bökenkamp
- Department of Paediatric Cardiology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Marianne Bootsma
- Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands
| | | | - Reinder Evertz
- Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Debby M E I Hellebrekers
- Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Yvonne M Hoedemaekers
- Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Jeroen Knijnenburg
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Ronald Lekanne Deprez
- Department of Human Genetics, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Anneke M van Mil
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Anneline S J M Te Riele
- Netherlands ACM Registry, Utrecht, The Netherlands
- Department of Heart and Lungs, Division of Cardiology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | | | - Arthur A M Wilde
- Heart Centre, Department of Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Sing-Chien Yap
- Department of Cardiology, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Dennis Dooijes
- Department of Clinical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Tamara T Koopmann
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - J Peter van Tintelen
- Netherlands ACM Registry, Utrecht, The Netherlands
- Department of Clinical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
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6
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Higo S. Disease modeling of desmosome-related cardiomyopathy using induced pluripotent stem cell-derived cardiomyocytes. World J Stem Cells 2023; 15:71-82. [PMID: 37007457 PMCID: PMC10052339 DOI: 10.4252/wjsc.v15.i3.71] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/10/2023] [Accepted: 03/17/2023] [Indexed: 03/23/2023] Open
Abstract
Cardiomyopathy is a pathological condition characterized by cardiac pump failure due to myocardial dysfunction and the major cause of advanced heart failure requiring heart transplantation. Although optimized medical therapies have been developed for heart failure during the last few decades, some patients with cardiomyopathy exhibit advanced heart failure and are refractory to medical therapies. Desmosome, which is a dynamic cell-to-cell junctional component, maintains the structural integrity of heart tissues. Genetic mutations in desmosomal genes cause arrhythmogenic cardiomyopathy (AC), a rare inheritable disease, and predispose patients to sudden cardiac death and heart failure. Recent advances in sequencing technologies have elucidated the genetic basis of cardiomyopathies and revealed that desmosome-related cardiomyopathy is concealed in broad cardiomyopathies. Among desmosomal genes, mutations in PKP2 (which encodes PKP2) are most frequently identified in patients with AC. PKP2 deficiency causes various pathological cardiac phenotypes. Human cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs) in combination with genome editing, which allows the precise arrangement of the targeted genome, are powerful experimental tools for studying disease. This review summarizes the current issues associated with practical medicine for advanced heart failure and the recent advances in disease modeling using iPSC-derived cardiomyocytes targeting desmosome-related cardiomyopathy caused by PKP2 deficiency.
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Affiliation(s)
- Shuichiro Higo
- Department of Medical Therapeutics for Heart Failure, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
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7
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Tsui H, van Kampen SJ, Han SJ, Meraviglia V, van Ham WB, Casini S, van der Kraak P, Vink A, Yin X, Mayr M, Bossu A, Marchal GA, Monshouwer-Kloots J, Eding J, Versteeg D, de Ruiter H, Bezstarosti K, Groeneweg J, Klaasen SJ, van Laake LW, Demmers JAA, Kops GJPL, Mummery CL, van Veen TAB, Remme CA, Bellin M, van Rooij E. Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy. Sci Transl Med 2023; 15:eadd4248. [PMID: 36947592 DOI: 10.1126/scitranslmed.add4248] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 03/01/2023] [Indexed: 03/24/2023]
Abstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiac disease. Many patients with ACM harbor mutations in desmosomal genes, predominantly in plakophilin-2 (PKP2). Although the genetic basis of ACM is well characterized, the underlying disease-driving mechanisms remain unresolved. Explanted hearts from patients with ACM had less PKP2 compared with healthy hearts, which correlated with reduced expression of desmosomal and adherens junction (AJ) proteins. These proteins were also disorganized in areas of fibrotic remodeling. In vitro data from human-induced pluripotent stem cell-derived cardiomyocytes and microtissues carrying the heterozygous PKP2 c.2013delC pathogenic mutation also displayed impaired contractility. Knockin mice carrying the equivalent heterozygous Pkp2 c.1755delA mutation recapitulated changes in desmosomal and AJ proteins and displayed cardiac dysfunction and fibrosis with age. Global proteomics analysis of 4-month-old heterozygous Pkp2 c.1755delA hearts indicated involvement of the ubiquitin-proteasome system (UPS) in ACM pathogenesis. Inhibition of the UPS in mutant mice increased area composita proteins and improved calcium dynamics in isolated cardiomyocytes. Additional proteomics analyses identified lysine ubiquitination sites on the desmosomal proteins, which were more ubiquitinated in mutant mice. In summary, we show that a plakophilin-2 mutation can lead to decreased desmosomal and AJ protein expression through a UPS-dependent mechanism, which preceded cardiac remodeling. These findings suggest that targeting protein degradation and improving desmosomal protein stability may be a potential therapeutic strategy for the treatment of ACM.
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Affiliation(s)
- Hoyee Tsui
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584 CT, Netherlands
| | - Sebastiaan Johannes van Kampen
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584 CT, Netherlands
| | - Su Ji Han
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584 CT, Netherlands
| | - Viviana Meraviglia
- Department of Anatomy and Embryology, University Medical Center, Leiden, 2333 ZA, Netherlands
| | - Willem B van Ham
- Department of Medical Physiology, University Medical Center Utrecht, 3584 CM, Netherlands
| | - Simona Casini
- Department of Clinical and Experimental Cardiology, University Medical Center Amsterdam, 1105 AZ, Netherlands
| | - Petra van der Kraak
- Department of Pathology, University Medical Center Utrecht, 3584 CX, Netherlands
| | - Aryan Vink
- Department of Pathology, University Medical Center Utrecht, 3584 CX, Netherlands
| | - Xiaoke Yin
- James Black Centre, King's College, University of London, WC2R 2LS London, UK
| | - Manuel Mayr
- James Black Centre, King's College, University of London, WC2R 2LS London, UK
| | - Alexandre Bossu
- Department of Medical Physiology, University Medical Center Utrecht, 3584 CM, Netherlands
| | - Gerard A Marchal
- Department of Clinical and Experimental Cardiology, University Medical Center Amsterdam, 1105 AZ, Netherlands
| | - Jantine Monshouwer-Kloots
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584 CT, Netherlands
| | - Joep Eding
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584 CT, Netherlands
| | - Danielle Versteeg
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584 CT, Netherlands
| | - Hesther de Ruiter
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584 CT, Netherlands
| | - Karel Bezstarosti
- Proteomics Center, Erasmus Medical Center Rotterdam, 3015 CN, Netherlands
| | - Judith Groeneweg
- Department of Cardiology, University Medical Center Utrecht, 3584 CX, Netherlands
| | - Sjoerd J Klaasen
- Oncode Institute, Hubrecht Institute, Royal Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584 CT, Netherlands
| | - Linda W van Laake
- Department of Cardiology, University Medical Center Utrecht, 3584 CX, Netherlands
| | - Jeroen A A Demmers
- Proteomics Center, Erasmus Medical Center Rotterdam, 3015 CN, Netherlands
| | - Geert J P L Kops
- Oncode Institute, Hubrecht Institute, Royal Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584 CT, Netherlands
| | - Christine L Mummery
- Department of Anatomy and Embryology, University Medical Center, Leiden, 2333 ZA, Netherlands
| | - Toon A B van Veen
- Department of Medical Physiology, University Medical Center Utrecht, 3584 CM, Netherlands
| | - Carol Ann Remme
- Department of Clinical and Experimental Cardiology, University Medical Center Amsterdam, 1105 AZ, Netherlands
| | - Milena Bellin
- Department of Anatomy and Embryology, University Medical Center, Leiden, 2333 ZA, Netherlands
| | - Eva van Rooij
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584 CT, Netherlands
- Department of Cardiology, University Medical Center Utrecht, 3584 CX, Netherlands
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8
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Wang C, Ramahdita G, Genin G, Huebsch N, Ma Z. Dynamic mechanobiology of cardiac cells and tissues: Current status and future perspective. BIOPHYSICS REVIEWS 2023; 4:011314. [PMID: 37008887 PMCID: PMC10062054 DOI: 10.1063/5.0141269] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 03/08/2023] [Indexed: 03/31/2023]
Abstract
Mechanical forces impact cardiac cells and tissues over their entire lifespan, from development to growth and eventually to pathophysiology. However, the mechanobiological pathways that drive cell and tissue responses to mechanical forces are only now beginning to be understood, due in part to the challenges in replicating the evolving dynamic microenvironments of cardiac cells and tissues in a laboratory setting. Although many in vitro cardiac models have been established to provide specific stiffness, topography, or viscoelasticity to cardiac cells and tissues via biomaterial scaffolds or external stimuli, technologies for presenting time-evolving mechanical microenvironments have only recently been developed. In this review, we summarize the range of in vitro platforms that have been used for cardiac mechanobiological studies. We provide a comprehensive review on phenotypic and molecular changes of cardiomyocytes in response to these environments, with a focus on how dynamic mechanical cues are transduced and deciphered. We conclude with our vision of how these findings will help to define the baseline of heart pathology and of how these in vitro systems will potentially serve to improve the development of therapies for heart diseases.
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Affiliation(s)
| | - Ghiska Ramahdita
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, USA
| | | | | | - Zhen Ma
- Authors to whom correspondence should be addressed: and
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9
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De Bortoli M, Meraviglia V, Mackova K, Frommelt LS, König E, Rainer J, Volani C, Benzoni P, Schlittler M, Cattelan G, Motta BM, Volpato C, Rauhe W, Barbuti A, Zacchigna S, Pramstaller PP, Rossini A. Modeling incomplete penetrance in arrhythmogenic cardiomyopathy by human induced pluripotent stem cell derived cardiomyocytes. Comput Struct Biotechnol J 2023; 21:1759-1773. [PMID: 36915380 PMCID: PMC10006475 DOI: 10.1016/j.csbj.2023.02.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 02/16/2023] [Accepted: 02/16/2023] [Indexed: 02/19/2023] Open
Abstract
Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are commonly used to model arrhythmogenic cardiomyopathy (ACM), a heritable cardiac disease characterized by severe ventricular arrhythmias, fibrofatty myocardial replacement and progressive ventricular dysfunction. Although ACM is inherited as an autosomal dominant disease, incomplete penetrance and variable expressivity are extremely common, resulting in different clinical manifestations. Here, we propose hiPSC-CMs as a powerful in vitro model to study incomplete penetrance in ACM. Six hiPSC lines were generated from blood samples of three ACM patients carrying a heterozygous deletion of exon 4 in the PKP2 gene, two asymptomatic (ASY) carriers of the same mutation and one healthy control (CTR), all belonging to the same family. Whole exome sequencing was performed in all family members and hiPSC-CMs were examined by ddPCR, western blot, Wes™ immunoassay system, patch clamp, immunofluorescence and RNASeq. Our results show molecular and functional differences between ACM and ASY hiPSC-CMs, including a higher amount of mutated PKP2 mRNA, a lower expression of the connexin-43 protein, a lower overall density of sodium current, a higher intracellular lipid accumulation and sarcomere disorganization in ACM compared to ASY hiPSC-CMs. Differentially expressed genes were also found, supporting a predisposition for a fatty phenotype in ACM hiPSC-CMs. These data indicate that hiPSC-CMs are a suitable model to study incomplete penetrance in ACM.
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Key Words
- ABC, active ß-catenin
- ACM, arrhythmogenic cardiomyopathy
- ASY, asymptomatic
- Arrhythmogenic cardiomyopathy
- BBB, bundle-branch block
- CMs, cardiomyocytes
- CTR, control
- Cx43, connexin-43
- DEGs, differentially expressed genes
- GATK, Genome Analysis Toolkit
- Human induced pluripotent stem cell derived cardiomyocytes
- ICD, implantable cardioverter-defibrillator
- ID, intercalated disk
- Incomplete penetrance
- LBB, left bundle-branch block
- MRI, magnetic resonance imagingmut, mutated
- NSVT, non-sustained ventricular tachycardia
- RV, right ventricle
- hiPSC, human induced pluripotent stem cell
- wt, wild type
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Affiliation(s)
- Marzia De Bortoli
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Viviana Meraviglia
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy.,Department of Anatomy and Embryology, Leiden University Medical Center, 2316 Leiden, the Netherlands
| | - Katarina Mackova
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Laura S Frommelt
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Eva König
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Johannes Rainer
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Chiara Volani
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy.,Universita` degli Studi di Milano, The Cell Physiology MiLab, Department of Biosciences, Milano, Italy
| | - Patrizia Benzoni
- Universita` degli Studi di Milano, The Cell Physiology MiLab, Department of Biosciences, Milano, Italy
| | - Maja Schlittler
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Giada Cattelan
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Benedetta M Motta
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Claudia Volpato
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Werner Rauhe
- San Maurizio Hospital, Department of Cardiology, Bolzano, Italy
| | - Andrea Barbuti
- Universita` degli Studi di Milano, The Cell Physiology MiLab, Department of Biosciences, Milano, Italy
| | - Serena Zacchigna
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cardiovascular Biology Laboratory, Trieste, Italy
| | - Peter P Pramstaller
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
| | - Alessandra Rossini
- Institute for Biomedicine (Affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy
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10
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Hylind RJ, Pereira AC, Quiat D, Chandler SF, Roston TM, Pu WT, Bezzerides VJ, Seidman JG, Seidman CE, Abrams DJ. Population Prevalence of Premature Truncating Variants in Plakophilin-2 and Association With Arrhythmogenic Right Ventricular Cardiomyopathy: A UK Biobank Analysis. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2022; 15:e003507. [PMID: 35536239 PMCID: PMC9400410 DOI: 10.1161/circgen.121.003507] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Truncating variants in the desmosomal gene PKP2 (PKP2tv) cause arrhythmogenic right ventricular cardiomyopathy (ARVC) yet display varied penetrance and expressivity. METHODS We identified individuals with PKP2tv from the UK Biobank (UKB) and determined the prevalence of an ARVC phenotype and other cardiovascular traits based on clinical and procedural data. The PKP2tv minor allelic frequency in the UKB was compared with a second cohort of probands with a clinical diagnosis of ARVC (ARVC cohort), with a figure of 1:5000 assumed for disease prevalence. In silico predictors of variant pathogenicity (combined annotation-dependent depletion and Splice AI [Illumina, Inc.]) were assessed. RESULTS PKP2tv were identified in 193/200 643 (0.10%) UKB participants, with 47 unique PKP2tv. Features consistent with ARVC were present in 3 (1.6%), leaving 190 with PKP2tv without manifest disease (UKB cohort; minor allelic frequency 4.73×10-4). The ARVC cohort included 487 ARVC probands with 144 distinct PKP2tv, with 25 PKP2tv common to both cohorts. The odds ratio for ARVC for the 25 common PKP2tv was 0.047 (95% CI, 0.001-0.268; P=2.43×10-6), and only favored ARVC (odds ratio >1) for a single variant, p.Arg79*. In silico variant analysis did not differentiate PKP2tv between the 2 cohorts. Atrial fibrillation was over-represented in the UKB cohort in those with PKP2tv (7.9% versus 4.3%; odds ratio, 2.11; P=0.005). CONCLUSIONS PKP2tv are prevalent in the population and associated with ARVC in only a small minority, necessitating a more detailed understanding of how PKP2tv cause ARVC in combination with associated genetic and environmental risk factors.
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Affiliation(s)
- Robyn J Hylind
- Inherited Cardiac Arrhythmia Program, Department of Cardiology, Boston Children's Hospital (R.J.H., D.Q., S.F.C., T.M.R., W.T.P., V.J.B., D.J.A.), Harvard Medical School, Boston MA
| | - Alexandre C Pereira
- Department of Genetics (A.C.P., D.Q., J.G.S., C.E.S.), Harvard Medical School, Boston MA
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, Brazil (A.C.P.)
| | - Daniel Quiat
- Inherited Cardiac Arrhythmia Program, Department of Cardiology, Boston Children's Hospital (R.J.H., D.Q., S.F.C., T.M.R., W.T.P., V.J.B., D.J.A.), Harvard Medical School, Boston MA
- Department of Genetics (A.C.P., D.Q., J.G.S., C.E.S.), Harvard Medical School, Boston MA
| | - Stephanie F Chandler
- Inherited Cardiac Arrhythmia Program, Department of Cardiology, Boston Children's Hospital (R.J.H., D.Q., S.F.C., T.M.R., W.T.P., V.J.B., D.J.A.), Harvard Medical School, Boston MA
| | - Thomas M Roston
- Inherited Cardiac Arrhythmia Program, Department of Cardiology, Boston Children's Hospital (R.J.H., D.Q., S.F.C., T.M.R., W.T.P., V.J.B., D.J.A.), Harvard Medical School, Boston MA
| | - William T Pu
- Inherited Cardiac Arrhythmia Program, Department of Cardiology, Boston Children's Hospital (R.J.H., D.Q., S.F.C., T.M.R., W.T.P., V.J.B., D.J.A.), Harvard Medical School, Boston MA
| | - Vassilios J Bezzerides
- Inherited Cardiac Arrhythmia Program, Department of Cardiology, Boston Children's Hospital (R.J.H., D.Q., S.F.C., T.M.R., W.T.P., V.J.B., D.J.A.), Harvard Medical School, Boston MA
| | - Jonathan G Seidman
- Department of Genetics (A.C.P., D.Q., J.G.S., C.E.S.), Harvard Medical School, Boston MA
| | - Christine E Seidman
- Department of Genetics (A.C.P., D.Q., J.G.S., C.E.S.), Harvard Medical School, Boston MA
- Cardiovascular Division, Brigham and Women's Hospital (C.E.S.), Harvard Medical School, Boston MA
- Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.)
| | - Dominic J Abrams
- Inherited Cardiac Arrhythmia Program, Department of Cardiology, Boston Children's Hospital (R.J.H., D.Q., S.F.C., T.M.R., W.T.P., V.J.B., D.J.A.), Harvard Medical School, Boston MA
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11
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Camors EM, Roth AH, Alef JR, Sullivan RD, Johnson JN, Purevjav E, Towbin JA. Progressive Reduction in Right Ventricular Contractile Function Attributable to Altered Actin Expression in an Aging Mouse Model of Arrhythmogenic Cardiomyopathy. Circulation 2022; 145:1609-1624. [PMID: 35437032 PMCID: PMC9133220 DOI: 10.1161/circulationaha.120.049261] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 03/18/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder of desmosomal dysfunction, and PKP2 (plakophilin-2) has been reported to be the most common disease-causing gene when mutation-positive. In the early concealed phase, the ACM heart is at high risk of sudden cardiac death before cardiac remodeling occurs because of mistargeted ion channels and altered Ca2+ handling. However, the results of pathogenic PKP2 variants on myocyte contraction in ACM pathogenesis remain unknown. METHODS We studied the outcomes of a human truncating variant of PKP2 on myocyte contraction using a novel knock-in mouse model with insertion of thymidine in exon 5 of Pkp2, which mimics a familial case of ACM (PKP2-L404fsX5). We used serial echocardiography, electrocardiography, blood pressure measurements, histology, cardiomyocyte contraction, intracellular calcium measurements, and gene and protein expression studies. RESULTS Serial echocardiography of Pkp2 heterozygous (Pkp2-Het) mice revealed progressive failure of the right ventricle (RV) in animals older than 3 months. By contrast, left ventricular function remained normal. ECGs of 6-month-old anesthetized Pkp2-Het mice showed normal baseline heart rates and QRS complexes. Cardiac responses to β-adrenergic agonist isoproterenol (2 mg/kg) plus caffeine (120 mg/kg) were also normal. However, adrenergic stimulation enhanced the susceptibility of Pkp2-Het hearts to tachyarrhythmia and sudden cardiac death. Histological staining showed no significant fibrosis or adipocyte infiltration in the RVs and left ventricles of 6- and 12-month-old Pkp2-Het hearts. Contractility assessment of isolated myocytes demonstrated progressively reduced Pkp2-Het RV cardiomyocyte function consistent with RV failure measured by echocardiography. However, aging Pkp2-Het and control RV myocytes loaded with intracellular Ca2+ indicator Fura-2 showed comparable Ca2+ transients. Western blotting of Pkp2-RV homogenates revealed a 40% decrease in actin, whereas actin immunoprecipitation followed by a 2,4-dinitrophenylhydrazine staining showed doubled oxidation level. This correlated with a 39% increase in troponin-I phosphorylation. In contrast, Pkp2-Het left ventricular myocytes had normal contraction, actin expression and oxidation, and troponin-I phosphorylation. Last, Western blotting of cardiac biopsies revealed that actin expression was 40% decreased in RVs of patients with end-stage ACM. CONCLUSIONS During the early concealed phase of ACM, reduced actin expression drives loss of RV myocyte contraction, contributing to progressive RV dysfunction.
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Affiliation(s)
- Emmanuel M. Camors
- Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN
- Children’s Foundation Research Institute, Le Bonheur Children’s Hospital, Memphis, TN
| | - Alyson H. Roth
- Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN
- Children’s Foundation Research Institute, Le Bonheur Children’s Hospital, Memphis, TN
| | - Joseph R. Alef
- Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN
- Children’s Foundation Research Institute, Le Bonheur Children’s Hospital, Memphis, TN
| | - Ryan D. Sullivan
- Department of Internal Medicine, University of Arizona College of Medicine, Phoenix, AR
| | - Jason N. Johnson
- Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN
- Children’s Foundation Research Institute, Le Bonheur Children’s Hospital, Memphis, TN
- Pediatric Cardiology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Enkhsaikhan Purevjav
- Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN
- Children’s Foundation Research Institute, Le Bonheur Children’s Hospital, Memphis, TN
| | - Jeffrey A. Towbin
- Heart Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN
- Children’s Foundation Research Institute, Le Bonheur Children’s Hospital, Memphis, TN
- Pediatric Cardiology, St. Jude Children’s Research Hospital, Memphis, TN
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12
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Vähätalo JH, Holmström LTA, Pylkäs K, Skarp S, Porvari K, Pakanen L, Kaikkonen KS, Perkiömäki JS, Kerkelä R, Huikuri HV, Myerburg RJ, Junttila MJ. Genetic Variants Associated With Sudden Cardiac Death in Victims With Single Vessel Coronary Artery Disease and Left Ventricular Hypertrophy With or Without Fibrosis. Front Cardiovasc Med 2022; 8:755062. [PMID: 35087879 PMCID: PMC8788946 DOI: 10.3389/fcvm.2021.755062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 12/07/2021] [Indexed: 11/26/2022] Open
Abstract
Objective: Cardiac hypertrophy with varying degrees of myocardial fibrosis is commonly associated with coronary artery disease (CAD) related sudden cardiac death (SCD), especially in young victims among whom patterns of coronary artery lesions do not entirely appear to explain the cause of SCD. Our aim was to study the genetic background of hypertrophy, with or without fibrosis, among ischemic SCD victims with single vessel CAD. Methods: The study population was derived from the Fingesture study, consisting of all autopsy-verified SCDs in Northern Finland between the years 1998 and 2017 (n = 5,869). We carried out targeted next-generation sequencing using a panel of 174 genes associated with myocardial structure and ion channel function in 95 ischemic-SCD victims (mean age 63.6 ± 10.3 years; 88.4% males) with single-vessel CAD in the absence of previously diagnosed CAD and cardiac hypertrophy with or without myocardial fibrosis at autopsy. Results: A total of 42 rare variants were detected in 43 subjects (45.3% of the study subjects). Five variants in eight subjects (8.4%) were classified as pathogenic or likely pathogenic. We observed 37 variants of uncertain significance in 39 subjects (40.6%). Variants were detected in myocardial structure protein coding genes, associated with arrhythmogenic right ventricular, dilated, hypertrophic and left ventricular non-compaction cardiomyopathies. Also, variants were detected in ryanodine receptor 2 (RYR2), a gene associated with both cardiomyopathies and catecholaminergic polymorphic ventricular tachycardias. Conclusions: Rare variants associated with cardiomyopathies, in the absence of anatomic evidence of the specific inherited cardiomyopathies, were common findings among CAD-related SCD victims with single vessel disease and myocardial hypertrophy found at autopsies, suggesting that these variants may modulate the risk for fatal arrhythmias and SCD in ischemic disease.
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Affiliation(s)
- Juha H. Vähätalo
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
- *Correspondence: Juha H. Vähätalo
| | - Lauri T. A. Holmström
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Katri Pylkäs
- Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Sini Skarp
- Research Unit of Biomedicine and Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Katja Porvari
- Department of Forensic Medicine, Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu, Oulu, Finland
| | - Lasse Pakanen
- Department of Forensic Medicine, Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu, Oulu, Finland
- Forensic Medicine Unit, Finnish Institute for Health and Welfare, Oulu, Finland
| | - Kari S. Kaikkonen
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Juha S. Perkiömäki
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Risto Kerkelä
- Research Unit of Biomedicine and Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Heikki V. Huikuri
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Robert J. Myerburg
- Division of Cardiology, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - M. Juhani Junttila
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
- Biocenter Oulu, University of Oulu, Oulu, Finland
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13
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Vallverdú-Prats M, Brugada R, Alcalde M. Premature Termination Codon in 5' Region of Desmoplakin and Plakoglobin Genes May Escape Nonsense-Mediated Decay through the Reinitiation of Translation. Int J Mol Sci 2022; 23:ijms23020656. [PMID: 35054841 PMCID: PMC8775493 DOI: 10.3390/ijms23020656] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/05/2022] [Accepted: 01/06/2022] [Indexed: 02/04/2023] Open
Abstract
Arrhythmogenic cardiomyopathy is a heritable heart disease associated with desmosomal mutations, especially premature termination codon (PTC) variants. It is known that PTC triggers the nonsense-mediated decay (NMD) mechanism. It is also accepted that PTC in the last exon escapes NMD; however, the mechanisms involving NMD escaping in 5′-PTC, such as reinitiation of translation, are less known. The main objective of the present study is to evaluate the likelihood that desmosomal genes carrying 5′-PTC will trigger reinitiation. HL1 cell lines were edited by CRISPR/Cas9 to generate isogenic clones carrying 5′-PTC for each of the five desmosomal genes. The genomic context of the ATG in-frame in the 5′ region of desmosomal genes was evaluated by in silico predictions. The expression levels of the edited genes were assessed by Western blot and real-time PCR. Our results indicate that the 5′-PTC in PKP2, DSG2 and DSC2 acts as a null allele with no expression, whereas in the DSP and JUP gene, N-truncated protein is expressed. In concordance with this, the genomic context of the 5′-region of DSP and JUP presents an ATG in-frame with an optimal context for the reinitiation of translation. Thus, 5′-PTC triggers NMD in the PKP2, DSG2* and DSC2 genes, whereas it may escape NMD through the reinitiation of the translation in DSP and JUP genes, with no major effects on ACM-related gene expression.
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Affiliation(s)
| | - Ramon Brugada
- Cardiovascular Genetics Center, IdIBGi, University of Girona, 17190 Girona, Spain;
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
- Medical Science Department, School of Medicine, University of Girona, 17071 Girona, Spain
- Cardiology Service Hospital, University of Girona, 17007 Girona, Spain
- Correspondence: (R.B.); (M.A.)
| | - Mireia Alcalde
- Cardiovascular Genetics Center, IdIBGi, University of Girona, 17190 Girona, Spain;
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
- Correspondence: (R.B.); (M.A.)
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14
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Inoue H, Nakamura S, Higo S, Shiba M, Kohama Y, Kondo T, Kameda S, Tabata T, Okuno S, Ikeda Y, Li J, Liu L, Yamazaki S, Takeda M, Ito E, Takashima S, Miyagawa S, Sawa Y, Hikoso S, Sakata Y. Modeling reduced contractility and impaired desmosome assembly due to plakophilin-2 deficiency using isogenic iPS cell-derived cardiomyocytes. Stem Cell Reports 2022; 17:337-351. [PMID: 35063130 PMCID: PMC8828557 DOI: 10.1016/j.stemcr.2021.12.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022] Open
Abstract
Loss-of-function mutations in PKP2, which encodes plakophilin-2, cause arrhythmogenic cardiomyopathy (AC). Restoration of deficient molecules can serve as upstream therapy, thereby requiring a human model that recapitulates disease pathology and provides distinct readouts in phenotypic analysis for proof of concept for gene replacement therapy. Here, we generated isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with precisely adjusted expression of plakophilin-2 from a patient with AC carrying a heterozygous frameshift PKP2 mutation. After monolayer differentiation, plakophilin-2 deficiency led to reduced contractility, disrupted intercalated disc structures, and impaired desmosome assembly in iPSC-CMs. Allele-specific fluorescent labeling of endogenous DSG2 encoding desmoglein-2 in the generated isogenic lines enabled real-time desmosome-imaging under an adjusted dose of plakophilin-2. Adeno-associated virus-mediated gene replacement of PKP2 recovered contractility and restored desmosome assembly, which was sequentially captured by desmosome-imaging in plakophilin-2-deficient iPSC-CMs. Our isogenic set of iPSC-CMs recapitulates AC pathology and provides a rapid and convenient cellular platform for therapeutic development.
Generation of isogenic iPSC-CMs with a precise dose of plakophilin-2 Modeling reduced contractility and impaired desmosome assembly using iPSC-CMs Generation of isogenic iPSC-CMs for desmosome-imaging Proof of concept of PKP2 replacement using isogenic plakophilin-2-deficient iPSC-CMs
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Affiliation(s)
- Hiroyuki Inoue
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | | | - Shuichiro Higo
- Department of Medical Therapeutics for Heart Failure, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
| | - Mikio Shiba
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Yasuaki Kohama
- Cardiovascular Division, National Hospital Organization, Osaka-Minami Medical Center, Kawachinagano, Osaka 586-8512, Japan
| | - Takumi Kondo
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Satoshi Kameda
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Tomoka Tabata
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Shota Okuno
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Yoshihiko Ikeda
- Department of Pathology, National Cerebral and Cardiovascular Center, Suita, Osaka 564-8565, Japan
| | - Junjun Li
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Department of Design for Tissue Regeneration, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Li Liu
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Department of Design for Tissue Regeneration, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Satoru Yamazaki
- Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka 564-8565, Japan
| | - Maki Takeda
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Emiko Ito
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Seiji Takashima
- Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Yoshiki Sawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Shungo Hikoso
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Yasushi Sakata
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
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15
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Cabrera-Borrego E, Montero-Vilchez T, Bermúdez-Jiménez FJ, Tercedor-Sánchez J, Tercedor-Sánchez L, Sánchez-Díaz M, Macías-Ruiz R, Molina-Jiménez M, Cañizares-García FJ, Fernández-Segura E, Fernandez-Flores A, Arias-Santiago S, Jiménez-Jáimez J. Heterozygous Arrhythmogenic Cardiomyopathy- desmoplakin Mutation Carriers Exhibit a Subclinical Cutaneous Phenotype with Cell Membrane Disruption and Lack of Intercellular Adhesion. J Clin Med 2021; 10:jcm10194608. [PMID: 34640625 PMCID: PMC8509745 DOI: 10.3390/jcm10194608] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/03/2021] [Accepted: 10/05/2021] [Indexed: 01/20/2023] Open
Abstract
Genetic variants that result in truncation in desmoplakin (DSP) are a known cause of arrhythmogenic cardiomyopathy (AC). In homozygous carriers, the combined involvement of skin and heart muscle is well defined, however, this is not the case in heterozygous carriers. The aim of this work is to describe cutaneous findings and analyze the molecular and ultrastructural cutaneous changes in this group of patients. Four women and eight men with a mean age of 48 ± 14 years were included. Eight met definitive criteria for AC, one was borderline and three were silent carriers. No relevant macroscopic changes in skin and hair were detected. However, significantly lower skin temperature (29.56 vs. 30.97 °C, p = 0.036) and higher transepidermal water loss (TEWL) (37.62 vs. 23.95 g m 2 h 1, p = 0.028) were observed compared to sex- and age-matched controls. Histopathology of the skin biopsy showed widening of intercellular spaces and acantholysis of keratinocytes in the spinous layer. Immunohistochemistry showed a strongly reduced expression of DSP in all samples. Trichogram showed regular nodules (thickening) compatible with pseudomonilethrix. Therefore, regardless of cardiac involvement, heterozygous patients with truncation-type variants in DSP have lower skin temperature and higher TEWL, constant microscopic skin involvement with specific patterns and pseudomonilethrix in the trichogram.
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Affiliation(s)
- Eva Cabrera-Borrego
- Cardiology Department, Hospital Universitario Virgen de las Nieves, 18014 Granada, CP, Spain; (E.C.-B.); (F.J.B.-J.); (L.T.-S.); (R.M.-R.); (M.M.-J.); (J.J.-J.)
- Instituto de Investigación Biosanitaria ibs. GRANADA, Universidad de Granada, 18012 Granada, CP, Spain; (T.M.-V.); (J.T.-S.); (M.S.-D.)
| | - Trinidad Montero-Vilchez
- Instituto de Investigación Biosanitaria ibs. GRANADA, Universidad de Granada, 18012 Granada, CP, Spain; (T.M.-V.); (J.T.-S.); (M.S.-D.)
- Dermatology Department, Hospital Universitario Virgen de las Nieves, 18014 Granada, CP, Spain
| | - Francisco José Bermúdez-Jiménez
- Cardiology Department, Hospital Universitario Virgen de las Nieves, 18014 Granada, CP, Spain; (E.C.-B.); (F.J.B.-J.); (L.T.-S.); (R.M.-R.); (M.M.-J.); (J.J.-J.)
- Instituto de Investigación Biosanitaria ibs. GRANADA, Universidad de Granada, 18012 Granada, CP, Spain; (T.M.-V.); (J.T.-S.); (M.S.-D.)
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, CP, Spain
| | - Jesús Tercedor-Sánchez
- Instituto de Investigación Biosanitaria ibs. GRANADA, Universidad de Granada, 18012 Granada, CP, Spain; (T.M.-V.); (J.T.-S.); (M.S.-D.)
- Dermatology Department, Hospital Universitario Virgen de las Nieves, 18014 Granada, CP, Spain
| | - Luis Tercedor-Sánchez
- Cardiology Department, Hospital Universitario Virgen de las Nieves, 18014 Granada, CP, Spain; (E.C.-B.); (F.J.B.-J.); (L.T.-S.); (R.M.-R.); (M.M.-J.); (J.J.-J.)
- Instituto de Investigación Biosanitaria ibs. GRANADA, Universidad de Granada, 18012 Granada, CP, Spain; (T.M.-V.); (J.T.-S.); (M.S.-D.)
| | - Manuel Sánchez-Díaz
- Instituto de Investigación Biosanitaria ibs. GRANADA, Universidad de Granada, 18012 Granada, CP, Spain; (T.M.-V.); (J.T.-S.); (M.S.-D.)
- Dermatology Department, Hospital Universitario Virgen de las Nieves, 18014 Granada, CP, Spain
| | - Rosa Macías-Ruiz
- Cardiology Department, Hospital Universitario Virgen de las Nieves, 18014 Granada, CP, Spain; (E.C.-B.); (F.J.B.-J.); (L.T.-S.); (R.M.-R.); (M.M.-J.); (J.J.-J.)
- Instituto de Investigación Biosanitaria ibs. GRANADA, Universidad de Granada, 18012 Granada, CP, Spain; (T.M.-V.); (J.T.-S.); (M.S.-D.)
| | - María Molina-Jiménez
- Cardiology Department, Hospital Universitario Virgen de las Nieves, 18014 Granada, CP, Spain; (E.C.-B.); (F.J.B.-J.); (L.T.-S.); (R.M.-R.); (M.M.-J.); (J.J.-J.)
- Instituto de Investigación Biosanitaria ibs. GRANADA, Universidad de Granada, 18012 Granada, CP, Spain; (T.M.-V.); (J.T.-S.); (M.S.-D.)
| | | | - Eduardo Fernández-Segura
- Department of Histology, University of Granada, 18016 Granada, CP, Spain; (F.J.C.-G.); (E.F.-S.)
| | | | - Salvador Arias-Santiago
- Instituto de Investigación Biosanitaria ibs. GRANADA, Universidad de Granada, 18012 Granada, CP, Spain; (T.M.-V.); (J.T.-S.); (M.S.-D.)
- Dermatology Department, Hospital Universitario Virgen de las Nieves, 18014 Granada, CP, Spain
- Correspondence:
| | - Juan Jiménez-Jáimez
- Cardiology Department, Hospital Universitario Virgen de las Nieves, 18014 Granada, CP, Spain; (E.C.-B.); (F.J.B.-J.); (L.T.-S.); (R.M.-R.); (M.M.-J.); (J.J.-J.)
- Instituto de Investigación Biosanitaria ibs. GRANADA, Universidad de Granada, 18012 Granada, CP, Spain; (T.M.-V.); (J.T.-S.); (M.S.-D.)
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16
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Burkard N, Meir M, Kannapin F, Otto C, Petzke M, Germer CT, Waschke J, Schlegel N. Desmoglein2 Regulates Claudin2 Expression by Sequestering PI-3-Kinase in Intestinal Epithelial Cells. Front Immunol 2021; 12:756321. [PMID: 34659262 PMCID: PMC8514949 DOI: 10.3389/fimmu.2021.756321] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 09/10/2021] [Indexed: 01/14/2023] Open
Abstract
Inflammation-induced reduction of intestinal desmosomal cadherin Desmoglein 2 (Dsg2) is linked to changes of tight junctions (TJ) leading to impaired intestinal epithelial barrier (IEB) function by undefined mechanisms. We characterized the interplay between loss of Dsg2 and upregulation of pore-forming TJ protein Claudin2. Intraperitoneal application of Dsg2-stablising Tandem peptide (TP) attenuated impaired IEB function, reduction of Dsg2 and increased Claudin2 in DSS-induced colitis in C57Bl/6 mice. TP blocked loss of Dsg2-mediated adhesion and upregulation of Claudin2 in Caco2 cells challenged with TNFα. In Dsg2-deficient Caco2 cells basal expression of Claudin2 was increased which was paralleled by reduced transepithelial electrical resistance and by augmented phosphorylation of AKTSer473 under basal conditions. Inhibition of phosphoinositid-3-kinase proved that PI-3-kinase/AKT-signaling is critical to upregulate Claudin2. In immunostaining PI-3-kinase dissociated from Dsg2 under inflammatory conditions. Immunoprecipitations and proximity ligation assays confirmed a direct interaction of Dsg2 and PI-3-kinase which was abrogated following TNFα application. In summary, Dsg2 regulates Claudin2 expression by sequestering PI-3-kinase to the cell borders in intestinal epithelium.
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Affiliation(s)
- Natalie Burkard
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery University Hospital Würzburg, Würzburg, Germany
| | - Michael Meir
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery University Hospital Würzburg, Würzburg, Germany
| | - Felix Kannapin
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery University Hospital Würzburg, Würzburg, Germany
| | - Christoph Otto
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery University Hospital Würzburg, Würzburg, Germany
| | - Maximilian Petzke
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery University Hospital Würzburg, Würzburg, Germany
| | - Christoph-Thomas Germer
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery University Hospital Würzburg, Würzburg, Germany
| | - Jens Waschke
- Institute of Anatomy and Cell Biology, Department I, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Nicolas Schlegel
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery University Hospital Würzburg, Würzburg, Germany
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17
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Vallverdú-Prats M, Alcalde M, Sarquella-Brugada G, Cesar S, Arbelo E, Fernandez-Falgueras A, Coll M, Pérez-Serra A, Puigmulé M, Iglesias A, Fiol V, Ferrer-Costa C, del Olmo B, Picó F, Lopez L, Jordà P, García-Álvarez A, Tirón de Llano C, Toro R, Grassi S, Oliva A, Brugada J, Brugada R, Campuzano O. Rare Variants Associated with Arrhythmogenic Cardiomyopathy: Reclassification Five Years Later. J Pers Med 2021; 11:162. [PMID: 33652588 PMCID: PMC7996798 DOI: 10.3390/jpm11030162] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 02/17/2021] [Accepted: 02/19/2021] [Indexed: 12/17/2022] Open
Abstract
Genetic interpretation of rare variants associated with arrhythmogenic cardiomyopathy (ACM) is essential due to their diagnostic implications. New data may relabel previous variant classifications, but how often reanalysis is necessary remains undefined. Five years ago, 39 rare ACM-related variants were identified in patients with features of cardiomyopathy. These variants were classified following the American College of Medical Genetics and Genomics' guidelines. In the present study, we reevaluated these rare variants including novel available data. All cases carried one rare variant classified as being of ambiguous significance (82.05%) or likely pathogenic (17.95%) in 2016. In our comprehensive reanalysis, the classification of 30.77% of these variants changed, mainly due to updated global frequencies. As in 2016, nowadays most variants were classified as having an uncertain role (64.1%), but the proportion of variants with an uncertain role was significantly decreased (17.95%). The percentage of rare variants classified as potentially deleterious increased from 17.95% to 23.07%. Moreover, 83.33% of reclassified variants gained certainty. We propose that periodic genetic reanalysis of all rare variants associated with arrhythmogenic cardiomyopathy should be undertaken at least once every five years. Defining the roles of rare variants may help clinicians obtain a definite diagnosis.
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Affiliation(s)
- Marta Vallverdú-Prats
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
| | - Mireia Alcalde
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.A.); (P.J.); (A.G.-Á.); (J.B.)
| | - Georgia Sarquella-Brugada
- Medical Science Department, School of Medicine, University of Girona, 17071 Girona, Spain;
- Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain; (S.C.); (V.F.)
| | - Sergi Cesar
- Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain; (S.C.); (V.F.)
| | - Elena Arbelo
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.A.); (P.J.); (A.G.-Á.); (J.B.)
- Arrhythmias Unit, Hospital Clinic de Barcelona, University of Barcelona, 08036 Barcelona, Spain
| | - Anna Fernandez-Falgueras
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
- Cardiology Service, Hospital Dr. Josep Trueta, University of Girona, 17007 Girona, Spain;
| | - Mónica Coll
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.A.); (P.J.); (A.G.-Á.); (J.B.)
| | - Alexandra Pérez-Serra
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.A.); (P.J.); (A.G.-Á.); (J.B.)
| | - Marta Puigmulé
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.A.); (P.J.); (A.G.-Á.); (J.B.)
| | - Anna Iglesias
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.A.); (P.J.); (A.G.-Á.); (J.B.)
| | - Victoria Fiol
- Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain; (S.C.); (V.F.)
| | - Carles Ferrer-Costa
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
| | - Bernat del Olmo
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.A.); (P.J.); (A.G.-Á.); (J.B.)
| | - Ferran Picó
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
| | - Laura Lopez
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
| | - Paloma Jordà
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.A.); (P.J.); (A.G.-Á.); (J.B.)
- Arrhythmias Unit, Hospital Clinic de Barcelona, University of Barcelona, 08036 Barcelona, Spain
| | - Ana García-Álvarez
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.A.); (P.J.); (A.G.-Á.); (J.B.)
- Arrhythmias Unit, Hospital Clinic de Barcelona, University of Barcelona, 08036 Barcelona, Spain
| | - Coloma Tirón de Llano
- Cardiology Service, Hospital Dr. Josep Trueta, University of Girona, 17007 Girona, Spain;
| | - Rocío Toro
- Medicine Department, School of Medicine, 11003 Cadiz, Spain;
| | - Simone Grassi
- Institute of Public Health, Section Legal Medicine, Catholic University, 00153 Rome, Italy; (S.G.); (A.O.)
| | - Antonio Oliva
- Institute of Public Health, Section Legal Medicine, Catholic University, 00153 Rome, Italy; (S.G.); (A.O.)
| | - Josep Brugada
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.A.); (P.J.); (A.G.-Á.); (J.B.)
- Arrhythmias Unit, Hospital Clinic de Barcelona, University of Barcelona, 08036 Barcelona, Spain
| | - Ramon Brugada
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.A.); (P.J.); (A.G.-Á.); (J.B.)
- Medical Science Department, School of Medicine, University of Girona, 17071 Girona, Spain;
- Cardiology Service, Hospital Dr. Josep Trueta, University of Girona, 17007 Girona, Spain;
| | - Oscar Campuzano
- Cardiovascular Genetics Center, University of Girona—IdIBGi, 17190 Girona, Spain; (M.V.-P.); (M.A.); (A.F.-F.); (M.C.); (A.P.-S.); (M.P.); (A.I.); (C.F.-C.); (B.d.O.); (F.P.); (L.L.)
- Centro Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.A.); (P.J.); (A.G.-Á.); (J.B.)
- Medical Science Department, School of Medicine, University of Girona, 17071 Girona, Spain;
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18
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Ghidoni A, Elliott PM, Syrris P, Calkins H, James CA, Judge DP, Murray B, Barc J, Probst V, Schott JJ, Song JP, Hauer RNW, Hoorntje ET, van Tintelen JP, Schulze-Bahr E, Hamilton RM, Mittal K, Semsarian C, Behr ER, Ackerman MJ, Basso C, Parati G, Gentilini D, Kotta MC, Mayosi BM, Schwartz PJ, Crotti L. Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2021; 14:e003097. [PMID: 33566628 DOI: 10.1161/circgen.120.003097] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM. METHODS A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2-positive probands, and clinical evaluation was performed. RESULTS Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%). CONCLUSIONS In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.
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Affiliation(s)
- Alice Ghidoni
- Center for Cardiac Arrhythmias of Genetic Origin (A.G., M.-C.K., P.J.S., L.C.), Istituto Auxologico Italiano, IRCCS, Milan, Italy
| | - Perry M Elliott
- Center for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, United Kingdom (P.M.E., P.S.)
| | - Petros Syrris
- Center for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, United Kingdom (P.M.E., P.S.)
| | - Hugh Calkins
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (H.C., C.A.J., B.M.)
| | - Cynthia A James
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (H.C., C.A.J., B.M.)
| | - Daniel P Judge
- Medical University of South Carolina, Charleston, SC (D.P.J.)
| | - Brittney Murray
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (H.C., C.A.J., B.M.)
| | - Julien Barc
- Université de Nantes (J.B.), CNRS, Inserm, l'Institut du Thorax, France
| | - Vincent Probst
- Université de Nantes, CHU Nantes (V.P., J.J.S.), CNRS, Inserm, l'Institut du Thorax, France.,Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart (V.P., E.S.-B., E.R.B., C.B., P.J.S., L.C.)
| | - Jean Jacques Schott
- Université de Nantes, CHU Nantes (V.P., J.J.S.), CNRS, Inserm, l'Institut du Thorax, France
| | - Jiang-Ping Song
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China (J.-P.S.)
| | - Richard N W Hauer
- Netherlands Heart Institute (R.N.W.H., E.T.H., J.P.v.T.), University Medical Center Utrecht.,Department of Cardiology (R.N.W.H.), University Medical Center Utrecht
| | - Edgar T Hoorntje
- Netherlands Heart Institute (R.N.W.H., E.T.H., J.P.v.T.), University Medical Center Utrecht.,Department of Genetics, University Medical Center Groningen, University of Groningen, the Netherlands (E.T.H.)
| | - J Peter van Tintelen
- Netherlands Heart Institute (R.N.W.H., E.T.H., J.P.v.T.), University Medical Center Utrecht.,Department of Genetics (J.P.v.T.), University Medical Center Utrecht
| | - Eric Schulze-Bahr
- Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart (V.P., E.S.-B., E.R.B., C.B., P.J.S., L.C.).,Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Germany (E.S.-B.)
| | | | - Kirti Mittal
- Hospital for Sick Children, Toronto, ON, Canada (R.M.H., K.M.)
| | - Christopher Semsarian
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, NSW, Australia (C.S.)
| | - Elijah R Behr
- Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart (V.P., E.S.-B., E.R.B., C.B., P.J.S., L.C.).,Cardiology Clinical Academic Group, Institute of Molecular and Clinical Sciences, St George's University of London, St George's University Hospitals NHS Foundation Trust, London, United Kingdom (E.R.B.)
| | - Michael J Ackerman
- Departments of Cardiovascular Medicine (Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (M.J.A.)
| | - Cristina Basso
- Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart (V.P., E.S.-B., E.R.B., C.B., P.J.S., L.C.).,Cardiovascular Pathology Unit, Department of Cardiac, Thoracic and Vascular Sciences, University and Hospital of Padua, Italy (C.B.)
| | - Gianfranco Parati
- Istituto Auxologico Italiano, IRCCS, Cardiomyopathies Unit, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan (G.P., L.C.).,Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy (G.P., L.C.)
| | - Davide Gentilini
- Bioinformatics and Statistical Genomics Unit (D.G.), Istituto Auxologico Italiano, IRCCS, Milan, Italy.,Department of Brain and Behavioural Sciences, University of Pavia, Italy (D.G.)
| | - Maria-Christina Kotta
- Center for Cardiac Arrhythmias of Genetic Origin (A.G., M.-C.K., P.J.S., L.C.), Istituto Auxologico Italiano, IRCCS, Milan, Italy
| | - Bongani M Mayosi
- Department of Medicine, Hatter Institute for Cardiovascular Research in Africa, Groote Schuur Hospital and Division of Cardiology, Faculty of Health Sciences, University of Cape Town, South Africa (B.M.M.)
| | - Peter J Schwartz
- Center for Cardiac Arrhythmias of Genetic Origin (A.G., M.-C.K., P.J.S., L.C.), Istituto Auxologico Italiano, IRCCS, Milan, Italy.,Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart (V.P., E.S.-B., E.R.B., C.B., P.J.S., L.C.)
| | - Lia Crotti
- Center for Cardiac Arrhythmias of Genetic Origin (A.G., M.-C.K., P.J.S., L.C.), Istituto Auxologico Italiano, IRCCS, Milan, Italy.,Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart (V.P., E.S.-B., E.R.B., C.B., P.J.S., L.C.).,Istituto Auxologico Italiano, IRCCS, Cardiomyopathies Unit, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan (G.P., L.C.).,Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy (G.P., L.C.)
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19
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Gerull B, Brodehl A. Genetic Animal Models for Arrhythmogenic Cardiomyopathy. Front Physiol 2020; 11:624. [PMID: 32670084 PMCID: PMC7327121 DOI: 10.3389/fphys.2020.00624] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 05/18/2020] [Indexed: 12/12/2022] Open
Abstract
Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell-cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.
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Affiliation(s)
- Brenda Gerull
- Comprehensive Heart Failure Center Wuerzburg, Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany.,Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada
| | - Andreas Brodehl
- Erich and Hanna Klessmann Institute for Cardiovascular Research and Development, Heart and Diabetes Center NRW, University Hospitals of the Ruhr-University of Bochum, Bad Oeynhausen, Germany
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20
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Zhao G, Zhang HM, Qiu Y, Ye X, Yang D. Cleavage of Desmosomal Cadherins Promotes γ-Catenin Degradation and Benefits Wnt Signaling in Coxsackievirus B3-Induced Destruction of Cardiomyocytes. Front Microbiol 2020; 11:767. [PMID: 32457708 PMCID: PMC7225294 DOI: 10.3389/fmicb.2020.00767] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 03/31/2020] [Indexed: 01/01/2023] Open
Abstract
Coxsackievirus B3 (CVB3) is the primary etiologic agent of viral myocarditis, a major heart disease that occurs predominantly in children and young adolescents. In the heart, intercalated disks (ICD) are important structural formations that connect adjacent cardiomyocytes to maintain cardiac architecture and mediate signal communication. Deficiency in ICD components, such as desmosome proteins, leads to heart dysfunction. γ-catenin, a component protein of desmosomes, normally binds directly to desmocollin-2 and desmoglein-2. In this study, we found that CVB3 infection downregulated γ-catenin at the protein level but not the mRNA level in mouse HL-1 cardiomyocytes. We further found that this reduction of γ-catenin protein is a result of ubiquitin proteasome-mediated degradation, since the addition of proteasome inhibitor MG132 inhibited γ-catenin downregulation. In addition, we found that desmocollin-2 and desmoglein-2 were cleaved by both viral protease 3C and virus-activated cellular caspase, respectively. These cleavages led to the release of bound γ-catenin from the desmosome into the cytosol, resulting in rapid degradation of γ-catenin. Since γ-catenin shares high sequence homology with β-catenin in binding the TCF/LEF transcription factor, we further studied the effect of γ-catenin degradation on Wnt/β-catenin signaling. Luciferase assay showed that γ-catenin expression inhibited Wnt/β-catenin signaling. This finding was substantiated by qPCR to show that overexpression of γ-catenin downregulated transcription of Wnt signal target genes, c-myc and MMP9, while silencing γ-catenin upregulated these target genes. Finally, we demonstrated that γ-catenin expression inhibited CVB3 replication. In search for the underlying mechanism, we found that silencing γ-catenin caused down-regulation of interferon-β and its stimulated antiviral genes MDA5, MAVS, and ISG15. Taken together, our results indicate, for the first time, that CVB3 infection causes cardiomyocyte death through, at least in part, direct damage to the desmosome structure and reduction of γ-catenin protein, which in return promotes Wnt/β-catenin signaling and downregulates interferon-β stimulated immune responses.
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Affiliation(s)
- Guangze Zhao
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
| | - Huifang M Zhang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
| | - Ye Qiu
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,College of Biology, Hunan University, Changsha, China
| | - Xin Ye
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
| | - Decheng Yang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada
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21
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Abstract
Intercalated discs (ICDs) are highly orchestrated structures that connect neighboring cardiomyocytes in the heart. Three major complexes are distinguished in ICD: desmosome, adherens junction (AJ), and gap junction (GJ). Desmosomes are major cell adhesion junctions that anchor cell membrane to the intermediate filament network; AJs connect the actin cytoskeleton of adjacent cells; and gap junctions metabolically and electrically connect the cytoplasm of adjacent cardiomyocytes. All these complexes work as a single unit, the so-called area composita, interdependently rather than individually. Mutation or altered expression of ICD proteins results in various cardiac diseases, such as ARVC (arrhythmogenic right ventricular cardiomyopathy), dilated cardiomyopathy, and hypotrophy cardiomyopathy, eventually leading to heart failure. In this article, we first review the recent findings on the structural organization of ICD and their functions and then focus on the recent advances in molecular pathogenesis of the ICD-related heart diseases, which include two major areas: i) the ICD gene mutations in cardiac diseases, and ii) the involvement of ICD proteins in signal transduction pathways leading to myocardium remodeling and eventual heart failure. These major ICD-related signaling pathways include Wnt/β-catenin pathway, p38 MAPK cascade, Rho-dependent serum response factor (SRF) signaling, calcineurin/NFAT signaling, Hippo kinase cascade, etc., which are differentially regulated in pathological conditions.
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22
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Chen K, Rao M, Guo G, Duru F, Chen L, Chen X, Song J, Hu S. Recessive variants in plakophilin-2 contributes to early-onset arrhythmogenic cardiomyopathy with severe heart failure. Europace 2019; 21:970-977. [PMID: 30830208 DOI: 10.1093/europace/euz026] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 02/11/2019] [Indexed: 11/12/2022] Open
Abstract
AIMS Plakophilin-2 (PKP2) is the most prevalent mutant gene causing arrhythmogenic cardiomyopathy (ACM) and PKP2 carriers are prone to develop ventricular arrhythmic events. The objective of this study is to use integrated analysis of whole genome sequencing (WGS) and transcriptome sequencing (RNAseq) to identify deep intronic and/or coding variants that cause aberrant splicing events in ACM patients, and hence, to test the hypothesis that recessive variants in PKP2 may lead to early-onset ACM with severe heart failure. METHODS AND RESULTS We performed WGS and RNAseq in 27 heart transplanted ACM patients. By integrated analysis of WGS/RNAseq, we discovered that two patients with PKP2 variants were affected in recessive pattern. One patient had aberrant splicing arising from two intronic variants that led to exon skipping and exon retention. We screened three additional recessive PKP2 variants in 47 non-heart transplanted ACM patients. We compared the clinical characteristics of recessive PKP2 (n = 5) and heterozygous PKP2 carriers (n = 18), and found that recessive PKP2 variant carriers all had early-onset ACM with left ventricular dysfunction. We examined truncating PKP2 variants in explanted hearts and confirmed that truncated PKP2 was not translated. Moreover, the morphology of intercalated disc in recessive PKP2 variants carriers was similar to normal heart suggesting little intercalated disc remodelling. CONCLUSION By using combined implementation of WGS RNAseq, we were able to demonstrate that recessive variants in PKP2 may contribute to early-onset ACM with severe heart failure. These findings may play a role in risk stratification of ACM based on genetic testing in clinical practice.
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Affiliation(s)
- Kai Chen
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science, 167 Beilishi Road, Xicheng District, Beijing, China
| | - Man Rao
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science, 167 Beilishi Road, Xicheng District, Beijing, China
| | - Guangran Guo
- Union Hospital, Tongji Medical College, Huangzhong University of Science and Technology, Wuhan, China
| | - Firat Duru
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science, 167 Beilishi Road, Xicheng District, Beijing, China.,Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland.,Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Liang Chen
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science, 167 Beilishi Road, Xicheng District, Beijing, China
| | - Xiao Chen
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science, 167 Beilishi Road, Xicheng District, Beijing, China
| | - Jiangping Song
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science, 167 Beilishi Road, Xicheng District, Beijing, China
| | - Shengshou Hu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science, 167 Beilishi Road, Xicheng District, Beijing, China
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23
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Whole-Exome Sequencing Identified a De Novo Mutation of Junction Plakoglobin (p.R577C) in a Chinese Patient with Arrhythmogenic Right Ventricular Cardiomyopathy. BIOMED RESEARCH INTERNATIONAL 2019; 2019:9103860. [PMID: 31275992 PMCID: PMC6558630 DOI: 10.1155/2019/9103860] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/21/2019] [Accepted: 04/28/2019] [Indexed: 11/18/2022]
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare and potentially life-threatening disorder of the heart. The clinical spectrum of ARVC includes myocyte loss and fibro-fatty tissue replacement. With the progress of ARVC, the patient can present serious ventricular arrhythmias, heart failure, and even sudden cardiac death. Previous studies have demonstrated that desmosomes and intermediate junctions play a crucial role in the generation and development of ARVC. In this study, we enrolled a Chinese patient with suspicious ARVC. The patient suffered from right ventricular enlargement and less thickening of right ventricular wall. ECG record showed an epsilon wave. However, there was no obvious symptom in his parents. After whole-exome sequencing and data filtering, we identified a de novo mutation (c.1729C>T/p.R577C) of junction plakoglobin (JUP) in this patient. Bioinformatics programs predicted that this mutation was deleterious. Western blot revealed that, compared to cells transfected with WT plasmids, the expressions of desmoglein 2 (DSG2) and Connexin 43 were decreased overtly in cells transfected with the mutant plasmid. Previous studies have proven that the reduction of DSG2 and Connexin 43 may disturb the stability of desmosomes. In this research, we reported a novel de novo mutation (c.1729C>T/p.R577C) of JUP in a Chinese patient with suspicious ARVC. Functional research further confirmed the pathogenicity of this novel mutation. Our study expanded the spectrum of JUP mutations and may contribute to the genetic diagnosis and counseling of patients with ARVC.
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24
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Maruthappu T, Posafalvi A, Castelletti S, Delaney PJ, Syrris P, O'Toole EA, Green KJ, Elliott PM, Lambiase PD, Tinker A, McKenna WJ, Kelsell DP. Loss-of-function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype. Br J Dermatol 2019; 180:1114-1122. [PMID: 30382575 DOI: 10.1111/bjd.17388] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND Arrhythmogenic cardiomyopathy (AC) is an inherited, frequently underdiagnosed disorder, which can predispose individuals to sudden cardiac death. Rare, recessive forms of AC can be associated with woolly hair and palmoplantar keratoderma, but most autosomal dominant AC forms have been reported to be cardiac specific. Causative mutations frequently occur in desmosomal genes including desmoplakin (DSP). OBJECTIVES In this study, we systematically investigated the presence of a skin and hair phenotype in heterozygous DSP mutation carriers with AC. METHODS Six AC pedigrees with 38 carriers of a dominant loss-of-function (nonsense or frameshift) mutation in DSP were evaluated by detailed clinical examination (cardiac, hair and skin) and molecular phenotyping. RESULTS All carriers with mutations affecting both major DSP isoforms (DSPI and II) were observed to have curly or wavy hair in the pedigrees examined, except for members of Family 6, where the position of the mutation only affected the cardiac-specific isoform DSPI. A mild palmoplantar keratoderma was also present in many carriers. Sanger sequencing of cDNA from nonlesional carrier skin suggested degradation of the mutant allele. Immunohistochemistry of patient skin demonstrated mislocalization of DSP and other junctional proteins (plakoglobin, connexin 43) in the basal epidermis. However, in Family 6, DSP localization was comparable with control skin. CONCLUSIONS This study identifies a highly recognizable cutaneous phenotype associated with dominant loss-of-function DSPI/II mutations underlying AC. Increased awareness of this phenotype among healthcare workers could facilitate a timely diagnosis of AC in the absence of overt cardiac features.
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Affiliation(s)
- T Maruthappu
- Blizard Institute, Queen Mary University of London, London, U.K
| | - A Posafalvi
- Blizard Institute, Queen Mary University of London, London, U.K
| | - S Castelletti
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy
| | - P J Delaney
- Blizard Institute, Queen Mary University of London, London, U.K
| | - P Syrris
- Institute of Cardiovascular Science, University College London, London, U.K
| | - E A O'Toole
- Blizard Institute, Queen Mary University of London, London, U.K
| | - K J Green
- Department of Pathology and Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A
| | - P M Elliott
- Department of Cardiac Electrophysiology, The Barts Heart Centre, St Bartholomew's Hospital, London, U.K
| | - P D Lambiase
- Institute of Cardiovascular Science, University College London, London, U.K.,Department of Cardiac Electrophysiology, The Barts Heart Centre, St Bartholomew's Hospital, London, U.K
| | - A Tinker
- The Heart Centre, Queen Mary University of London, London, U.K
| | - W J McKenna
- Department of Cardiac Electrophysiology, The Barts Heart Centre, St Bartholomew's Hospital, London, U.K
| | - D P Kelsell
- Blizard Institute, Queen Mary University of London, London, U.K
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25
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Sommariva E, Stadiotti I, Perrucci GL, Tondo C, Pompilio G. Cell models of arrhythmogenic cardiomyopathy: advances and opportunities. Dis Model Mech 2018; 10:823-835. [PMID: 28679668 PMCID: PMC5536909 DOI: 10.1242/dmm.029363] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Arrhythmogenic cardiomyopathy is a rare genetic disease that is mostly inherited as an autosomal dominant trait. It is associated predominantly with mutations in desmosomal genes and is characterized by the replacement of the ventricular myocardium with fibrous fatty deposits, arrhythmias and a high risk of sudden death. In vitro studies have contributed to our understanding of the pathogenic mechanisms underlying this disease, including its genetic determinants, as well as its cellular, signaling and molecular defects. Here, we review what is currently known about the pathogenesis of arrhythmogenic cardiomyopathy and focus on the in vitro models that have advanced our understanding of the disease. Finally, we assess the potential of established and innovative cell platforms for elucidating unknown aspects of this disease, and for screening new potential therapeutic agents. This appraisal of in vitro models of arrhythmogenic cardiomyopathy highlights the discoveries made about this disease and the uses of these models for future basic and therapeutic research. Summary:In vitro models of ACM provide insights into the molecular mechanisms of this disease. This reappraisal offers a comprehensive vision of past discoveries and constitutes a tool for future research.
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Affiliation(s)
- Elena Sommariva
- Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, via Parea 4, Milan 20138, Italy
| | - Ilaria Stadiotti
- Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, via Parea 4, Milan 20138, Italy
| | - Gianluca L Perrucci
- Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, via Parea 4, Milan 20138, Italy.,Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Festa del Perdono 7, Milan 20122, Italy
| | - Claudio Tondo
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Festa del Perdono 7, Milan 20122, Italy.,Cardiac Arrhythmia Research Center, Centro Cardiologico Monzino-IRCCS, via Parea 4, Milan 20138, Italy
| | - Giulio Pompilio
- Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, via Parea 4, Milan 20138, Italy.,Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Festa del Perdono 7, Milan 20122, Italy
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26
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Mazurek SR, Calway T, Harmon C, Farrell P, Kim GH. MicroRNA-130a Regulation of Desmocollin 2 in a Novel Model of Arrhythmogenic Cardiomyopathy. Microrna 2018; 6:143-150. [PMID: 27834139 DOI: 10.2174/2211536605666161109111031] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 10/17/2016] [Accepted: 10/27/2016] [Indexed: 01/27/2023]
Abstract
BACKGROUND MicroRNAs are small noncoding RNA molecules that play a critical role in regulating physiological and disease processes. Recent studies have now recognized microRNAs as an important player in cardiac arrhythmogenesis. Molecular insight into arrhythmogenic cardiomyopathy (AC) has primarily focused on mutations in desmosome proteins. To our knowledge, models of AC due to microRNA dysregulation have not been reported. Previously, we reported on miR-130a mediated down-regulation of Connexin43. OBJECTIVE Here, we investigate miR-130a-mediated translational repression of Desmocollin2 (DSC2), as it has a predicted target site for miR-130a. DSC2 is an important protein for cell adhesion, which has been shown to be dysregulated in human AC. METHOD & RESULTS After induction of miR-130a, transgenic mice demonstrated right ventricular dilation. Surface ECG revealed spontaneous premature ventricular complexes confirming an arrhythmogenic phenotype in αMHC-miR130a mice. Using total protein from whole ventricular lysate, western blot analysis demonstrated an 80% reduction in DSC2 levels in transgenic myocardium. Furthermore, immunofluorescent staining confirmed downregulation of DSC2 in transgenic compared with littermate control myocardium. In transgenic hearts, histologic findings revealed fibrosis and lipid accumulation within both ventricles. To validate DSC2 as a direct target of miR-130a, we performed in vitro target assays in 3T3 fibroblasts, known to express miR-130a. Using a luciferase reporter fused to the 3UTR of DSC2 compared with a control, we found a 42% reduction in luciferase activity with the DSC2 3UTR. This reduction was reversed upon selective inhibition of miR-130a. CONCLUSION Overexpression of miR-130a results in a disease phenotype characteristic of AC and therefore, may serve as potential model for microRNA-induced AC.
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Affiliation(s)
- Stefan R Mazurek
- Department of Medicine, University of Chicago, Chicago, IL 60637. United States
| | - Tyler Calway
- Department of Medicine, University of Chicago, Chicago, IL 60637. United States
| | - Cynthia Harmon
- Department of Medicine, University of Chicago, Chicago, IL 60637. United States
| | - Priyanka Farrell
- Department of Medicine, University of Chicago, Chicago, IL 60637. United States
| | - Gene H Kim
- Department of Medicine, University of Chicago, Chicago, IL 60637. United States
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27
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Pomerantz DJ, Ferdinandusse S, Cogan J, Cooper DN, Reimschisel T, Robertson A, Bican A, McGregor T, Gauthier J, Millington DS, Andrae JLW, Tschannen MR, Helbling DC, Demos WM, Denis S, Wanders RJA, Newman JN, Hamid R, Phillips JA, UDN. Clinical heterogeneity of mitochondrial NAD kinase deficiency caused by a NADK2 start loss variant. Am J Med Genet A 2018; 176:692-698. [PMID: 29388319 PMCID: PMC6185736 DOI: 10.1002/ajmg.a.38602] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 12/13/2017] [Accepted: 12/16/2017] [Indexed: 11/12/2022]
Abstract
Mitochondrial NAD kinase deficiency (NADK2D, OMIM #615787) is a rare autosomal recessive disorder of NADPH biosynthesis that can cause hyperlysinemia and dienoyl-CoA reductase deficiency (DECRD, OMIM #616034). NADK2 deficiency has been reported in only three unrelated patients. Two had severe, unremitting disease; one died at 4 months and the other at 5 years of age. The third was a 10 year old female with CNS anomalies, ataxia, and incoordination. In two cases mutations in NADK2 have been demonstrated. Here, we report the fourth known case, a 15 year old female with normal intelligence and a mild clinical and biochemical phenotype presumably without DECRD. Her clinical symptoms, which are now stable, became evident at the age of 9 with the onset of decreased visual acuity, bilateral optic atrophy, nystagmus, episodic lower extremity weakness, peripheral neuropathy, and gait abnormalities. Plasma amino acid levels were within normal limits except for mean lysine and proline levels that were 3.7 and 2.5 times the upper limits of normal. Whole exome sequencing (WES) revealed homozygosity for a g.36241900 A>G p. Met1Val start loss mutation in the primary NADK2 transcript (NM_001085411.1) encoding the 442 amino acid isoform. This presumed hypomorphic mutation has not been previously reported and is absent from the v1000GP, EVS, and ExAC databases. Our patient's normal intelligence and stable disease expands the clinical heterogeneity and the prognosis associated with NADK2 deficiency. Our findings also clarify the mechanism underlying NADK2 deficiency and suggest that this disease should be ruled out in cases of hyperlysinemia, especially those with visual loss, and neurological phenotypes.
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Affiliation(s)
- Daniel J. Pomerantz
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Sacha Ferdinandusse
- Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands
| | - Joy Cogan
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - David N. Cooper
- Institute of Medical Genetics, School of Medicine, Heath Park, Cardiff University, Cardiff, United Kingdom
| | - Tyler Reimschisel
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Amy Robertson
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Anna Bican
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Tracy McGregor
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jackie Gauthier
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - David S. Millington
- Department of Pediatrics, Duke University Medical Center, Durham, North Carolina
| | | | | | | | | | - Simone Denis
- Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands
| | - Ronald J. A. Wanders
- Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands
| | - John N. Newman
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Rizwan Hamid
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - John A. Phillips
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
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28
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Dueker ND, Guo S, Beecham A, Wang L, Blanton SH, Di Tullio MR, Rundek T, Sacco RL. Sequencing of Linkage Region on Chromosome 12p11 Identifies PKP2 as a Candidate Gene for Left Ventricular Mass in Dominican Families. G3 (BETHESDA, MD.) 2018; 8:659-668. [PMID: 29288195 PMCID: PMC5919734 DOI: 10.1534/g3.117.300358] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 12/10/2017] [Indexed: 12/16/2022]
Abstract
Increased left ventricular mass (LVM) is an intermediate phenotype for cardiovascular disease (CVD) and a predictor of stroke. Using families from the Dominican Republic, we have previously shown LVM to be heritable and found evidence for linkage to chromosome 12p11. Our current study aimed to further characterize the QTL by sequencing the 1 LOD unit down region in 10 families from the Dominican Republic with evidence for linkage to LVM. Within this region, we tested 5477 common variants [CVs; minor allele frequency (MAF) ≥5%] using the Quantitative Transmission-Disequilibrium Test (QTDT). Gene-based analyses were performed to test rare variants (RVs; MAF < 5%) in 181 genes using the family-based sequence kernel association test. A sample of 618 unrelated Dominicans from the Northern Manhattan Study (NOMAS) and 12 Dominican families with Exome Array data were used for replication analyses. The most strongly associated CV with evidence for replication was rs1046116 (Discovery families P = 9.0 × 10-4; NOMAS P = 0.03; replication families P = 0.46), a missense variant in PKP2 In nonsynonymous RV analyses, PKP2 was one of the most strongly associated genes (P = 0.05) with suggestive evidence for replication in NOMAS (P = 0.05). PKP2 encodes the plakophilin 2 protein and is a desmosomal gene implicated in arrythmogenic right ventricular cardiomyopathy and recently in arrhythmogenic left ventricular cardiomyopathy, which makes PKP2 an excellent candidate gene for LVM. In conclusion, sequencing of our previously reported QTL identified common and rare variants within PKP2 to be associated with LVM. Future studies are necessary to elucidate the role these variants play in influencing LVM.
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Affiliation(s)
- Nicole D Dueker
- John P. Hussman Institute for Human Genomics, University of Miami, Florida 33136
| | - Shengru Guo
- John P. Hussman Institute for Human Genomics, University of Miami, Florida 33136
| | - Ashley Beecham
- John P. Hussman Institute for Human Genomics, University of Miami, Florida 33136
| | - Liyong Wang
- John P. Hussman Institute for Human Genomics, University of Miami, Florida 33136
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Florida 33136
| | - Susan H Blanton
- John P. Hussman Institute for Human Genomics, University of Miami, Florida 33136
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Florida 33136
| | - Marco R Di Tullio
- Department of Medicine, Columbia University, New York, New York 10032
| | - Tatjana Rundek
- Department of Neurology, Miller School of Medicine, University of Miami, Florida 33136
- Department of Public Health Sciences, Miller School of Medicine, University of Miami, Florida 33136
| | - Ralph L Sacco
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Florida 33136
- Department of Neurology, Miller School of Medicine, University of Miami, Florida 33136
- Department of Public Health Sciences, Miller School of Medicine, University of Miami, Florida 33136
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Genetic and epigenetic regulation of arrhythmogenic cardiomyopathy. Biochim Biophys Acta Mol Basis Dis 2017; 1863:2064-2069. [PMID: 28454914 DOI: 10.1016/j.bbadis.2017.04.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 04/11/2017] [Accepted: 04/22/2017] [Indexed: 12/26/2022]
Abstract
Arrhythmogenic cardiomyopathy (AC) is most commonly characterized as a disease of the intercalated disc that promotes abnormal cardiac conduction. Previously, arrhythmogenic cardiomyopathy was frequently referred to as arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D); however, genotype-phenotype studies have defined a broader phenotypic spectrum; with the identification of left-dominant and biventricular subtypes. Molecular insight into AC has primarily focused on mutations in desmosomal proteins and the downstream signaling pathways; however, desmosomal gene mutations can only be identified in approximately 50% of patients with AC. Animal and cellular studies have shown that in addition to abnormal biomechanical properties from changes in desmosome function, crosstalk from the desmosome to the nucleus, gap junctions, and ion channels are implicated in the pathobiology of AC. In this review, we highlight some of the newly identified genetic and epigenetic mechanisms that may lead to the development of AC including the role of the Hippo pathway and microRNAs. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang.
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Ardesjö-Lundgren B, Tengvall K, Bergvall K, Farias FHG, Wang L, Hedhammar Å, Lindblad-Toh K, Andersson G. Comparison of cellular location and expression of Plakophilin-2 in epidermal cells from nonlesional atopic skin and healthy skin in German shepherd dogs. Vet Dermatol 2017; 28:377-e88. [PMID: 28386956 PMCID: PMC5516137 DOI: 10.1111/vde.12441] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2016] [Indexed: 12/25/2022]
Abstract
Background Canine atopic dermatitis (CAD) is an inflammatory and pruritic allergic skin disease caused by interactions between genetic and environmental factors. Previously, a genome‐wide significant risk locus on canine chromosome 27 for CAD was identified in German shepherd dogs (GSDs) and Plakophilin‐2 (PKP2) was defined as the top candidate gene. PKP2 constitutes a crucial component of desmosomes and also is important in signalling, metabolic and transcriptional activities. Objectives The main objective was to evaluate the role of PKP2 in CAD by investigating PKP2 expression and desmosome structure in nonlesional skin from CAD‐affected (carrying the top GWAS SNP risk allele) and healthy GSDs. We also aimed at defining the cell types in the skin that express PKP2 and its intracellular location. Animals/Methods Skin biopsies were collected from nine CAD‐affected and five control GSDs. The biopsies were frozen for immunofluorescence and fixed for electron microscopy immunolabelling and morphology. Results We observed the novel finding of PKP2 expression in dendritic cells and T cells in dog skin. Moreover, we detected that PKP2 was more evenly expressed within keratinocytes compared to its desmosomal binding‐partner plakoglobin. PKP2 protein was located in the nucleus and on keratin filaments attached to desmosomes. No difference in PKP2 abundance between CAD cases and controls was observed. Conclusion Plakophilin‐2 protein in dog skin is expressed in both epithelial and immune cells; based on its subcellular location its functional role is implicated in both nuclear and structural processes.
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Affiliation(s)
- Brita Ardesjö-Lundgren
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, BMC, Uppsala University, Box 582, SE-75123, Uppsala, Sweden.,Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Box 7023, SE-75007, Uppsala, Sweden
| | - Katarina Tengvall
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, BMC, Uppsala University, Box 582, SE-75123, Uppsala, Sweden.,Neuroimmunology Unit, Centrum for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, 17176, Stockholm, Sweden
| | - Kerstin Bergvall
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Box 7054, SE-75007, Uppsala, Sweden
| | - Fabiana H G Farias
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, BMC, Uppsala University, Box 582, SE-75123, Uppsala, Sweden
| | - Liya Wang
- Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Box 7011, SE-75007, Uppsala, Sweden
| | - Åke Hedhammar
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Box 7054, SE-75007, Uppsala, Sweden
| | - Kerstin Lindblad-Toh
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, BMC, Uppsala University, Box 582, SE-75123, Uppsala, Sweden.,Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA
| | - Göran Andersson
- Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Box 7023, SE-75007, Uppsala, Sweden
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Moncayo-Arlandi J, Guasch E, Sanz-de la Garza M, Casado M, Garcia NA, Mont L, Sitges M, Knöll R, Buyandelger B, Campuzano O, Diez-Juan A, Brugada R. Molecular disturbance underlies to arrhythmogenic cardiomyopathy induced by transgene content, age and exercise in a truncated PKP2 mouse model. Hum Mol Genet 2016; 25:3676-3688. [PMID: 27412010 DOI: 10.1093/hmg/ddw213] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 06/27/2016] [Accepted: 06/29/2016] [Indexed: 09/13/2023] Open
Abstract
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. We developed a transgenic mouse model containing a truncated PKP2 (PKP2-Ser329) and generated three transgenic lines expressing increasing transgene content. The pathophysiological features of ACM in this model were assessed. While we did not observe fibro-fatty replacement, ultrastructural defects were exhibited. Moreover, we observed transgene content-dependent development of structural (ventricle dilatation and dysfunction) and electrophysiological anomalies in mice (PR interval and QRS prolongation and arrhythmia induction). In concordance with pathological defects, we detected a content reduction and remodeling of the structural proteins Desmocollin-2, Plakoglobin, native Plakophilin-2, Desmin and β-Catenin as well as the electrical coupling proteins Connexin 43 and cardiac sodium channel (Nav1.5). Surprisingly, we observed structural but not electrophysiological abnormalities only in trained and old mice. We demonstrated that truncated PKP2 provokes ACM in the absence of fibro-fatty replacement in the mouse. Transgene dose is essential to reveal the pathology, whereas aging and endurance training trigger limited phenotype. Molecular abnormalities underlay the structural and electrophysiological defects.
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Affiliation(s)
- Javier Moncayo-Arlandi
- Cardiovascular Genetic Centre, Institute of Biomedical Research of Girona (IDIBGI), Girona, Spain
- Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain
| | - Eduard Guasch
- Arrhythmia Unit, Cardiology Department, Hospital Clínic, Universitat de Barcelona and IDIBAPS
| | - Maria Sanz-de la Garza
- Imaging Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona and IDIBAPS, Barcelona, Catalonia, Spain
| | - Marta Casado
- Institute of Biomedicine of Valencia, IBV-CSIC, Valencia, Spain
| | - Nahuel Aquiles Garcia
- Mixed unit for Cardiovascular Repair, Instituto de Investigación Sanitaria La Fe-Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Lluis Mont
- Arrhythmia Unit, Cardiology Department, Hospital Clínic, Universitat de Barcelona and IDIBAPS
| | - Marta Sitges
- Imaging Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona and IDIBAPS, Barcelona, Catalonia, Spain
| | - Ralph Knöll
- Department of Medicine, Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Huddinge, Sweden
| | - Byambajav Buyandelger
- Department of Medicine, Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Huddinge, Sweden
| | - Oscar Campuzano
- Cardiovascular Genetic Centre, Institute of Biomedical Research of Girona (IDIBGI), Girona, Spain
- Medical Science Department, School of Medicine, University of Girona
| | | | - Ramon Brugada
- Cardiovascular Genetic Centre, Institute of Biomedical Research of Girona (IDIBGI), Girona, Spain,
- Medical Science Department, School of Medicine, University of Girona
- Cardiovascular Genetics Clinic, Hospital Josep Trueta, Girona, Spain
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Tengvall K, Kozyrev S, Kierczak M, Bergvall K, Farias FHG, Ardesjö-Lundgren B, Olsson M, Murén E, Hagman R, Leeb T, Pielberg G, Hedhammar Å, Andersson G, Lindblad-Toh K. Multiple regulatory variants located in cell type-specific enhancers within the PKP2 locus form major risk and protective haplotypes for canine atopic dermatitis in German shepherd dogs. BMC Genet 2016; 17:97. [PMID: 27357287 PMCID: PMC4928279 DOI: 10.1186/s12863-016-0404-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 06/20/2016] [Indexed: 12/30/2022] Open
Abstract
Background Canine atopic dermatitis (CAD) is a chronic inflammatory skin disease triggered by allergic reactions involving IgE antibodies directed towards environmental allergens. We previously identified a ~1.5 Mb locus on canine chromosome 27 associated with CAD in German shepherd dogs (GSDs). Fine-mapping indicated association closest to the PKP2 gene encoding plakophilin 2. Results Additional genotyping and association analyses in GSDs combined with control dogs from five breeds with low-risk for CAD revealed the top SNP 27:19,086,778 (p = 1.4 × 10−7) and a rare ~48 kb risk haplotype overlapping the PKP2 gene and shared only with other high-risk CAD breeds. We selected altogether nine SNPs (four top-associated in GSDs and five within the ~48 kb risk haplotype) that spanned ~280 kb forming one risk haplotype carried by 35 % of the GSD cases and 10 % of the GSD controls (OR = 5.1, p = 5.9 × 10−5), and another haplotype present in 85 % of the GSD cases and 98 % of the GSD controls and conferring a protective effect against CAD in GSDs (OR = 0.14, p = 0.0032). Eight of these SNPs were analyzed for transcriptional regulation using reporter assays where all tested regions exerted regulatory effects on transcription in epithelial and/or immune cell lines, and seven SNPs showed allelic differences. The DNA fragment with the top-associated SNP 27:19,086,778 displayed the highest activity in keratinocytes with 11-fold induction of transcription by the risk allele versus 8-fold by the control allele (pdifference = 0.003), and also mapped close (~3 kb) to an ENCODE skin-specific enhancer region. Conclusions Our experiments indicate that multiple CAD-associated genetic variants located in cell type-specific enhancers are involved in gene regulation in different cells and tissues. No single causative variant alone, but rather multiple variants combined in a risk haplotype likely contribute to an altered expression of the PKP2 gene, and possibly nearby genes, in immune and epithelial cells, and predispose GSDs to CAD. Electronic supplementary material The online version of this article (doi:10.1186/s12863-016-0404-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Katarina Tengvall
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
| | - Sergey Kozyrev
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Marcin Kierczak
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Kerstin Bergvall
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Fabiana H G Farias
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Brita Ardesjö-Lundgren
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.,Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Mia Olsson
- Department of Medicine, Rheumatology Unit, Karolinska Institute, Stockholm, Sweden
| | - Eva Murén
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Ragnvi Hagman
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Tosso Leeb
- Institute of Genetics, University of Bern, Bern, Switzerland
| | - Gerli Pielberg
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Åke Hedhammar
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Göran Andersson
- Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Kerstin Lindblad-Toh
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.,Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Pilichou K, Thiene G, Bauce B, Rigato I, Lazzarini E, Migliore F, Perazzolo Marra M, Rizzo S, Zorzi A, Daliento L, Corrado D, Basso C. Arrhythmogenic cardiomyopathy. Orphanet J Rare Dis 2016; 11:33. [PMID: 27038780 PMCID: PMC4818879 DOI: 10.1186/s13023-016-0407-1] [Citation(s) in RCA: 110] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 03/16/2016] [Indexed: 01/16/2023] Open
Abstract
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. AC-causing genes mostly encode major components of the cardiac desmosome and up to 50 % of AC probands harbor mutations in one of them. Mutations in non-desmosomal genes have been also described in a minority of AC patients, predisposing to the same or an overlapping disease phenotype. Compound/digenic heterozygosity was identified in up to 25 % of AC-causing desmosomal gene mutation carriers, in part explaining the phenotypic variability. Abnormal trafficking of intercellular proteins to the intercalated discs of cardiomyocytes and Wnt/beta catenin and Hippo signaling pathways have been implicated in disease pathogenesis. AC is a major cause of sudden death in the young and in athletes. The clinical picture may include a sub-clinical phase; an overt electrical disorder; and right ventricular or biventricular pump failure. Ventricular fibrillation can occur at any stage. Genotype-phenotype correlation studies led to identify biventricular and dominant left ventricular variants, thus supporting the use of the broader term AC. Since there is no “gold standard” to reach the diagnosis of AC, multiple categories of diagnostic information have been combined and the criteria recently updated, to improve diagnostic sensitivity while maintaining specificity. Among diagnostic tools, contrast enhanced cardiac magnetic resonance is playing a major role in detecting left dominant forms of AC, even preceding morpho-functional abnormalities. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, sarcoidosis, dilated cardiomyopathy, right ventricular infarction, congenital heart diseases with right ventricular overload and athlete heart. A positive genetic test in the affected AC proband allows early identification of asymptomatic carriers by cascade genetic screening of family members. Risk stratification remains a major clinical challenge and antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator are the currently available therapeutic tools. Sport disqualification is life-saving, since effort is a major trigger not only of electrical instability but also of disease onset and progression. We review the current knowledge of this rare cardiomyopathy, suggesting a flowchart for primary care clinicians and geneticists.
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Affiliation(s)
- Kalliopi Pilichou
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Gaetano Thiene
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Barbara Bauce
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Ilaria Rigato
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Elisabetta Lazzarini
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Federico Migliore
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | | | - Stefania Rizzo
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Alessandro Zorzi
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Luciano Daliento
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Domenico Corrado
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | - Cristina Basso
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
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Akdis D, Medeiros-Domingo A, Gaertner-Rommel A, Kast JI, Enseleit F, Bode P, Klingel K, Kandolf R, Renois F, Andreoletti L, Akdis CA, Milting H, Lüscher TF, Brunckhorst C, Saguner AM, Duru F. Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls. Heart Rhythm 2015; 13:731-41. [PMID: 26569459 DOI: 10.1016/j.hrthm.2015.11.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Indexed: 11/15/2022]
Abstract
BACKGROUND Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is mainly an autosomal dominant disease characterized by fibrofatty infiltration of the right ventricle, leading to ventricular arrhythmias. Mutations in desmosomal proteins can be identified in about half of the patients. The pathogenic mechanisms leading to disease expression remain unclear. OBJECTIVE The purpose of this study was to investigate myocardial expression profiles of candidate molecules involved in the pathogenesis of ARVC/D. METHODS Myocardial messenger RNA (mRNA) expression of 62 junctional molecules, 5 cardiac ion channel molecules, 8 structural molecules, 4 apoptotic molecules, and 6 adipogenic molecules was studied. The averaged expression of candidate mRNAs was compared between ARVC/D samples (n = 10), nonfamilial dilated cardiomyopathy (DCM) samples (n = 10), and healthy control samples (n = 8). Immunohistochemistry and quantitative protein expression analysis were performed. Genetic analysis using next generation sequencing was performed in all patients with ARVC/D. RESULTS Following mRNA levels were significantly increased in patients with ARVC/D compared to those with DCM and healthy controls: phospholamban (P ≤ .001 vs DCM; P ≤ .001 vs controls), healthy tumor protein 53 apoptosis effector (P = .001 vs DCM; P ≤ .001 vs controls), and carnitine palmitoyltransferase 1β (P ≤ .001 vs DCM; P = 0.008 vs controls). Plakophillin-2 (PKP-2) mRNA was downregulated in patients with ARVC/D with PKP-2 mutations compared with patients with ARVC/D without PKP-2 mutations (P = .04). Immunohistochemistry revealed significantly increased protein expression of phospholamban, tumor protein 53 apoptosis effector, and carnitine palmitoyltransferase 1β in patients with ARVC/D and decreased PKP-2 expression in patients with ARVC/D carrying a PKP-2 mutation. CONCLUSION Changes in the expression profiles of sarcolemmal calcium channel regulation, apoptosis, and adipogenesis suggest that these molecular pathways may play a critical role in the pathogenesis of ARVC/D, independent of the underlying genetic mutations.
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Affiliation(s)
- Deniz Akdis
- Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland
| | - Argelia Medeiros-Domingo
- Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland; Department of Cardiology, University Hospital Bern, Bern, Switzerland
| | | | - Jeannette I Kast
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Frank Enseleit
- Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland
| | - Peter Bode
- Department of Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Karin Klingel
- Department of Molecular Pathology, University Hospital Tübingen, Tübingen, Germany
| | - Reinhard Kandolf
- Department of Molecular Pathology, University Hospital Tübingen, Tübingen, Germany
| | - Fanny Renois
- Laboratoire de Virologie Médicale et Moléculaire, EA 4684 CardioVir, Faculté de Médecine et CHU Robert Debré, Reims, France
| | - Laurent Andreoletti
- Laboratoire de Virologie Médicale et Moléculaire, EA 4684 CardioVir, Faculté de Médecine et CHU Robert Debré, Reims, France
| | - Cezmi A Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Hendrik Milting
- Department of Cardiology, University Hospital Bern, Bern, Switzerland
| | - Thomas F Lüscher
- Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland; Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Corinna Brunckhorst
- Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland
| | - Ardan M Saguner
- Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland
| | - Firat Duru
- Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland; Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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35
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Gerull B. Skin-heart connection: what can the epidermis tell us about the myocardium in arrhythmogenic cardiomyopathy? ACTA ACUST UNITED AC 2015; 7:225-7. [PMID: 24951656 DOI: 10.1161/circgenetics.114.000647] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Brenda Gerull
- From the Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
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Lazzarini E, Jongbloed JDH, Pilichou K, Thiene G, Basso C, Bikker H, Charbon B, Swertz M, van Tintelen JP, van der Zwaag PA. The ARVD/C genetic variants database: 2014 update. Hum Mutat 2015; 36:403-10. [PMID: 25676813 DOI: 10.1002/humu.22765] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 02/05/2015] [Indexed: 12/19/2022]
Abstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by myocardial atrophy, fibro-fatty replacement, and a high risk of ventricular arrhythmias that lead to sudden death. In 2009, genetic data from 57 publications were collected in the arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) Genetic Variants Database (freeware available at http://www.arvcdatabase.info), which comprised 481 variants in eight ACM-associated genes. In recent years, deep genetic sequencing has increased our knowledge of the genetics of ACM, revealing a large spectrum of nucleotide variations for which pathogenicity needs to be assessed. As of April 20, 2014, we have updated the ARVD/C database into the ARVD/C database to contain more than 1,400 variants in 12 ACM-related genes (PKP2, DSP, DSC2, DSG2, JUP, TGFB3, TMEM43, LMNA, DES, TTN, PLN, CTNNA3) as reported in more than 160 references. Of these, only 411 nucleotide variants have been reported as pathogenic, whereas the significance of the other approximately 1,000 variants is still unknown. This comprehensive collection of ACM genetic data represents a valuable source of information on the spectrum of ACM-associated genes and aims to facilitate the interpretation of genetic data and genetic counseling.
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Affiliation(s)
- Elisabetta Lazzarini
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Broussard JA, Getsios S, Green KJ. Desmosome regulation and signaling in disease. Cell Tissue Res 2015; 360:501-12. [PMID: 25693896 DOI: 10.1007/s00441-015-2136-5] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 01/21/2015] [Indexed: 01/10/2023]
Abstract
Desmosomes are cell-cell adhesive organelles with a well-known role in forming strong intercellular adhesion during embryogenesis and in adult tissues subject to mechanical stress, such as the heart and skin. More recently, desmosome components have also emerged as cell signaling regulators. Loss of expression or interference with the function of desmosome molecules results in diseases of the heart and skin and contributes to cancer progression. However, the underlying molecular mechanisms that result in inherited and acquired disorders remain poorly understood. To address this question, researchers are directing their studies towards determining the functions that occur inside and outside of the junctions and the extent to which functions are adhesion-dependent or independent. This review focuses on recent discoveries that provide insights into the role of desmosomes and desmosome components in cell signaling and disease; wherever possible, we address molecular functions within and outside of the adhesive structure.
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Affiliation(s)
- Joshua A Broussard
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
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