Exercise Triggers ARVC Phenotype in Mice Expressing a Disease-Causing Mutated Version of Human Plakophilin-2

Cruz, Francisco M.; Sanz-Rosa, David; Roche-Molina, Marta; García‐Prieto, Jaime; García-Ruiz, José M.; Pizarro, Gonzalo; Jiménez-Borreguero, Luis Jesús; Torres, Miguel; Bernad, António; Ruı́z-Cabello, Jesús; Fuster, Valentín; Ibáñez, Borja; Bernal, Juan A.

doi:10.1016/j.jacc.2015.01.045

Cited by 120 publications

(114 citation statements)

References 41 publications

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“…ARVC/D is inherited as an autosomal dominant or recessive condition. Currently, some pathogenic genes have been identified in ARVC/D, including desmocollin-2 (DSC2), desmoglein-2 (DSG2), transmembrance protein-43 (TMEM43), plakophilin-2 (PKP2), desmoplakin (DSP), ryanodine receptor-2, plakoglobin (JUP), desmin (DES), titin, transforming growth factor-β 3 (TGFβ 3 ), phospholamban, lamin A/C (LAMA), and catenin-α-3 [1,2,3,4]. Patients who carry more than one mutation have worse clinical prognoses, an earlier symptom onset, a first sustained arrhythmia, and an increased risk of developing left ventricular dysfunction and heart failure [5].…”

Section: Introductionmentioning

confidence: 99%

Whole Genome Sequence Identified a Rare Homozygous Pathogenic Mutation of the DSG2 Gene in a Familial Arrhythmogenic Cardiomyopathy Involving Both Ventricles

Lin

Zhang²,

Zhong³

et al. 2017

Cardiology

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Background: This study was designed to identify the pathogenic mutation in a Chinese family with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) using whole genome sequencing (WGS). Methods and Results: Probands II:1 and II:2 underwent routine examinations for diagnosis. Genomic DNA was extracted from the peripheral blood of family members and analyzed using WGS. A total of 60,285 single-nucleotide polymorphisms (SNP) and 13,918 insertions/deletions (InDel) occurring in the exonic regions of genes and predisposing to cardiomyopathies and arrhythmias were identified. When filtered using the 1000 Genomes Project (2014 version), NHLBI ESP6500, and ExAC databases, 12 missense SNP and 2 InDel in exonic regions remained, the allele frequencies of which were <0.01 or unknown. The potentially pathogenic mutations that occurred in the genes DSG2, PKP4, PRKAG2, FOXD4, CTTN, and DMD, which were identified by SIFT or PolyPhen-2 software as “damaging,” were validated using Sanger sequencing. Probands II:1 and II:2 shared an extremely rare homozygous mutation in the DSG2 (p.F531C) gene, which was also demonstrated using intersection analysis of WGS data from probands II:1 and II:2. Electron microscopy and histological staining of myocardial biopsies showed widened and destroyed intercalated discs, and interrupted, atrophic, and disarranged myocardial fibers, and hyperplastic interstitial fibers, collagen fibers, and adipocytes were infiltrated and invaded. Conclusions: A homozygous mutation of DSG2 p.F531C was identified as the pathogenic mutation in patients with ARVC/D involving both ventricles, as a result of widened and impaired intercalated discs, interrupted myocardial fibers, and abnormally hyperplastic interstitial fibers, collagen fibers, and adipocytes.

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Section: Introductionmentioning

confidence: 99%

Whole Genome Sequence Identified a Rare Homozygous Pathogenic Mutation of the DSG2 Gene in a Familial Arrhythmogenic Cardiomyopathy Involving Both Ventricles

Lin

Zhang²,

Zhong³

et al. 2017

Cardiology

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“…Several mouse models have been developed for Dsg2 [15, 20–22, 36], Jup [12, 23, 13, 37], Pkp2 [16, 24, 38], Dsp [17] and Des [39] showing either early embryonic lethality or different cardiac pathologies.…”

Section: Discussionmentioning

confidence: 99%

“…However, embryonic lethality caused by global knock-out of Jup [12, 13], Dsp [14], Dsg2 [15] and Pkp2 [16] demonstrated on one hand the general importance of those desmosomal proteins, but limited on the other hand functional analyses in vivo . To circumvent those limitations, several conditional knock-out, knock-in or transgenic mouse models for Dsp [17–19], Dsg2 [20–22], Jup [23] and Pkp2 [16, 24] have been developed, which mimic partially an AC phenotype. In contrast, complete Dsc2 knock-out did not induce a cardiac phenotype in mice under normal housing conditions [25].…”

Section: Introductionmentioning

confidence: 99%

Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling

et al. 2017

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BackgroundArrhythmogenic cardiomyopathy is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure, mainly as a result of mutations in cardiac desmosomal genes. Desmosomes are cell-cell junctions mediating adhesion of cardiomyocytes; however, the molecular and cellular mechanisms underlying the disease remain widely unknown. Desmocollin-2 is a desmosomal cadherin serving as an anchor molecule required to reconstitute homeostatic intercellular adhesion with desmoglein-2. Cardiac specific lack of desmoglein-2 leads to severe cardiomyopathy, whereas overexpression does not. In contrast, the corresponding data for desmocollin-2 are incomplete, in particular from the view of protein overexpression. Therefore, we developed a mouse model overexpressing desmocollin-2 to determine its potential contribution to cardiomyopathy and intercellular adhesion pathology.Methods and resultsWe generated transgenic mice overexpressing DSC2 in cardiac myocytes. Transgenic mice developed a severe cardiac dysfunction over 5 to 13 weeks as indicated by 2D-echocardiography measurements. Corresponding histology and immunohistochemistry demonstrated fibrosis, necrosis and calcification which were mainly localized in patches near the epi- and endocardium of both ventricles. Expressions of endogenous desmosomal proteins were markedly reduced in fibrotic areas but appear to be unchanged in non-fibrotic areas. Furthermore, gene expression data indicate an early up-regulation of inflammatory and fibrotic remodeling pathways between 2 to 3.5 weeks of age.ConclusionCardiac specific overexpression of desmocollin-2 induces necrosis, acute inflammation and patchy cardiac fibrotic remodeling leading to fulminant biventricular cardiomyopathy.

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“…Competitive athletic activity and strenuous physical activity are forbidden since not only may they induce a life-threatening ventricular arrhythmia but may also enhance disease progression (Cruz, et al, 2015;James, et al, 2013;Saberniak, et al, 2014). -blockers or antiarrhythmic drugs such as sotalol or amiodarone are often used for arrhythmia control and prevention.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Inherited cardiomyopathies—Novel therapies

Leviner

Hochhauser

Arad

2015

Pharmacology & Therapeutics

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Exercise Triggers ARVC Phenotype in Mice Expressing a Disease-Causing Mutated Version of Human Plakophilin-2

Cited by 120 publications

References 41 publications

Whole Genome Sequence Identified a Rare Homozygous Pathogenic Mutation of the DSG2 Gene in a Familial Arrhythmogenic Cardiomyopathy Involving Both Ventricles

Whole Genome Sequence Identified a Rare Homozygous Pathogenic Mutation of the DSG2 Gene in a Familial Arrhythmogenic Cardiomyopathy Involving Both Ventricles

Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling

Inherited cardiomyopathies—Novel therapies

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