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• W2920172761 abstract "Background. Arrhythmogenic cardiomyopathy (AC) is an inherited myocardial disease characterized by fibro-fatty replacement of the myocardium and life-threatening arrhythmias. This genetically and phenotypically heterogeneous condition, caused mainly by mutations in desmosomal genes (JUP, DSP, PKP2, DSG2 and DSC2), exhibits reduced penetrance making challenging the diagnosis and the identification of a molecular mechanism underlying disease pathogenesis.Aims. (1) To identify one or more altered molecular pathways in AC carriers of desmosomal mutations; (2) to evaluate the diagnostic role of JUP immune analysis in AC; (3) to study the frequency of genetic variants in the five major AC-related genes in a healthy population of Veneto region in order to evaluate their role in the pathogenesis of the disease.Materials and methods. (1) Differential expression analysis was carried out on myocardial tissue of 7 transplanted AC patients harbouring a pathogenic mutation in desmosomal genes and 3 controls. Genetic/epigenetic interference-factors were unbiased analyzing also 3 mouse groups: 8 over-expressing NS-dsg2 mutation [TgNS], 6 over-expressing wild type dsg2 [TgWt] and 2Wt); each group was further subdivided in two age-groups ( 3 weeks) before and after the onset of disease. Data confirmation was obtained by quantitative-PCR.(2) Heart specimens (HS, either autopsy or transplants) and endomyocardial biopsies (EMB) formalin-fixed from 44 AC unrelated patients and 30 non-AC matched-subjects were evaluated both by conventional immunoperoxidase analysis (IPOX) and immunofluorescence (IF) using two different JUP antibody (Ab) dilutions. Reduced JUP signal level was defined as 50% reduction in distribution and/or intensity of the immunostained areas compared to the control samples. To exclude time-dependent tissue decay, control staining for N-Cadherin was also performed.(3) 200 unrelated young athletes (mean age 20 yrs, male/female ratio 3:1), eligible at the pre-participation clinical evaluation, underwent conventional genetic screening for major disease causative genes. Variants selection was based on the current ACMG guidelines and the absence or low frequency (minor allele frequency, MAF <0.0002) of the genetic variants in the general population.Results. (1) 1136 and 822 differentially expressed genes (DEGs) were respectively identified in the right and left human myocardium of AC compared to controls. 204 DEGs were identified comparing TgNS 3 weeks gene expression profiling. 82 DEGs were identified comparing human and murine (TgNS>3 weeks) expression-profiling including genes most associated with canonical WNT/β-catenin and TGF-β pathways. On the contrary only 29 DEGs were identified in the comparison between TgNS<2 weeks to age-matched controls (WT and TgWt <2 weeks) mostly associated with inflammatory and pro-apoptotic process, but none with WNT and TGF-β pathways.(2) Test sensitivity (Se) of 70.6% and specificity (Sp) of 50%, with an Ab dilution 1:50.000 were found among HS, whereas with a 5-fold higher (1:250.000) Ab dilution the test Se was increased to 79.4% and the Sp decreased to 35%. Same analysis was performed on EMB samples showing different results: 40% Se; 80% Sp with 1:50.000 Ab dilution, whereas Se was 50% and Sp 70% with 1:250.000 Ab dilution. IF data were similar both with 1:1000 and 1:50.000 JUP-Ab dilution, indicating a Se of 61.8% and a Sp of 45% Sp in HS and a Se 50% and a Sp 70% in EMB samples.(3) Genetic screening identified rare genetic desmosomal variants in 20 healthy subjects (10%) reduced to 12 (6%) after appropriate filtering.Conclusions. Our findings demonstrated the interaction between WNT and TGF pathways at early disease stages, triggering cardiac remodelling. Specifically, we identified probably the ‘culprit molecules’ of disease onset. Routine IPOX and IF analysis of JUP signal is associated with low Se and limited Sp to be advocated as a diagnostic test. The absolute Se range was much higher in HS than EMB samples. The same for IF, HS specimens showed higher Se and lower Sp than EMB samples. Finally, high Ab dilutions confer higher Se but reduce test Sp.Comprehensive mutation screening and filtering in a large cohort of unrelated consecutive healthy subjects identified a lower rate of rare variants than the rates (16 and 18%) reported in literature for AC probably due to our selected cohort of healthy subjects." @default.
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• W2920172761 date "2018-01-13" @default.
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• W2920172761 title "Application of omic technologies in Arrhythmogenic Cardiomyopathy" @default.
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