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Cason, Marco (2018) Application of omic technologies in Arrhythmogenic Cardiomyopathy. [Ph.D. thesis]

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Abstract (english)

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 (<2 weeks and >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<2 weeks and 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.

Abstract (italian)

Introduzione. La cardiomiopatia aritmogena (AC) è una patologia ereditaria del miocardio caratterizzata da sostituzione fibrosa e adiposa dei cardiomiociti e da aritmie potenzialmente letali. Questa condizione geneticamente e fenotipicamente eterogenea, causata principalmente da varianti genetiche a livello dei geni desmosomiali (JUP, DSP, PKP2, DSG2 e DSC2), mostra una penetranza incompleta; queste caratteristiche rendono difficile non solo la corretta diagnosi, ma anche l'identificazione di un meccanismo molecolare alla base della patogenesi della malattia.
Obiettivi. (1) Identificare uno o più pathway molecolari alterati in pazienti AC portatori di mutazioni desmosomiali; (2) valutare il ruolo diagnostico dell'analisi immunologica della JUP; (3) studiare la frequenza delle varianti genetiche nei cinque principali geni correlati alla malattia in una popolazione sana della regione Veneto al fine di valutare il loro ruolo nella patogenesi dell’AC.
Materiali e metodi. (1) L'analisi dell'espressione differenziale è stata condotta su tessuto miocardico di 7 pazienti AC precedentementi sottoposti a trapianto cardiaco, portatori di una variante patogena nei geni desmosomiali e 3 controlli. Al fine di eliminare i fattori di interferenza genetica/epigenetica sono stati analizzati anche 3 gruppi di un modello murino: 8 topi sovra-esprimenti la mutazione NS-dsg2 [TgNS], 6 sovra-esprimenti la dsg2 wild-type [TgWt] e 2 Wt; ciascun gruppo è stato ulteriormente suddiviso in base all’età (<2 settimane e >3 settimane) prima e dopo l'insorgenza della malattia. La conferma dei dati è stata ottenuta mediante PCR quantitativa.
(2) Le analisi immunoistochimiche sono state eseguite sia su sezioni di miocardio (HS, autoptici o da trapianto) che su biopsie endomiocardiche (EMB) di 44 pazienti con diagnosi di AC e 30 soggetti non-AC. Tutti i casi sono stati valutati sia mediante colorazione con immunoperossidasi (IPOX) che mediante immunofluorescenza (IF) utilizzando due diverse diluizioni dell'anticorpo (Ab) che lega specificatamente la proteina JUP. Per escludere il decadimento tissutale tempo dipendente, è stata anche eseguita l’analisi di controllo sulla N-Caderina.
(3) Lo screening genetico convenzionale per i principali geni responsabili delle patologia è stato eseguito su 200 giovani atleti (età media 20 anni, rapporto maschi / femmine 3: 1), considerati idonei all’attività sportiva. La selezione delle varianti era basata sulle attuali linee guida della ACMG e sull'assenza/bassa frequenza (frequenza allelica minore, MAF <0,0002) delle varianti genetiche nella popolazione generale.
Risultati. (1) 1136 e 822 geni differenzialmente espressi (DEGs) sono stati identificati rispettivamente nel ventricolo destro e nel ventricolo sinistro dei pazienti AC. Sono stati identificati inoltre, 204 DEGs comparando il profilo di espressione genica di TgNS<2 settimane e TgNS> 3 settimane. Infine, confrontando il profilo di espressione umano con quello murino sono stati identificati 82 DEGs in comune; molti di questi geni sono associati ai pathway WNT e TGF-β. Al contrario, solo 29 DEGs sono stati identificati nel confronto tra TgNS <2 settimane e i controlli di età corrispondente (WT e TgWt <2 settimane); questi geni sono per lo più associati a processi infiammatori e pro-apoptotici, ma nessuno ai pathway WNT e TGF-β.
(2) L’analisi IPOX eseguita sui campioni HS con una diluizione dell’Ab 1: 50.000 mostra una sensibilità (Se) del 70,6% e la specificità (Sp) del 50%, mentre con una diluizione Ab 5 volte più alta (1: 250.000) la Se del test aumenta al 79,4% e la Sp diminuisce al 35%. La stessa analisi eseguita su campioni EMB restituisce come risultato: 40% Se; 80% Sp con diluizione anticorpale di 1: 50.000, mentre alla diluizione 1: 250.000 la Se si attesta a 50% e la Sp al 70%. I dati risultanti dall’analisi IF sono simili sia con diluizione dell’anticorpo 1: 1000 che 1: 50.000, indicando una Se del 61.8% e una Sp del 45% per gli HS e una Se 50% e una Sp 70% nei campioni EMB.
(3) Lo screening genetico dei 5 geni desmosomiali ha identificato varianti genetiche rare in 20 soggetti sani (10%) ridotti a 12 (6%) dopo un appropriato filtraggio.
Conclusioni. I nostri risultati hanno dimostrato l'interazione tra WNT e TGF-β nelle fasi iniziali della malattia, determinando il rimodellamento cardiaco. Nello specifico, abbiamo identificato probabilmente le "molecole colpevoli" dell'insorgenza della malattia.
L'analisi del segnale immunologico della JUP mostra in generale una bassa Se e ad una limitata Sp. Nello specifico, nell’analisi la Se risulta più elevata nei campioni HS rispetto ai campioni EMB. Alte diluizioni anticorpali conferiscono valori di Se superiori ma riducono la Sp del test.
Lo screening genetico e la successiva analisi delle varianti individuate in un'ampia coorte di soggetti sani ha identificato un tasso minore di varianti rare rispetto a quanto riportato in letteratura per la AC (16 e 18%), probabilmente ciò è dovuto alla pre-selezione fatta sui soggetti inseriti nella coorte analizzata.

EPrint type:Ph.D. thesis
Tutor:Pilichou, Kalliopi
Ph.D. course:Ciclo 30 > Corsi 30 > MEDICINA SPECIALISTICA "G.B. MORGAGNI"
Data di deposito della tesi:13 January 2018
Anno di Pubblicazione:13 January 2018
Key Words:Arrhythmogenic Cardiomyopathy, Cardiomiopatia aritmogena, Transcriptome, pathogenesis
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/11 Malattie dell'apparato cardiovascolare
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Istituti > Istituto di Anatomia Patologica
Codice ID:10745
Depositato il:09 Nov 2018 16:49
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