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Smaniotto, Gessica (2009) Ricerca di mutazioni patogene nella cardiomiopatia ipertrofica: nuovi dati e prospettive. [Ph.D. thesis]

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Abstract (english)

Hypertrophic cardiomyopathy (HCM) is the major cause of sudden cardiac death, with about 0.2% frequency in the adult human population. The disease, inherited as autosomal dominant, is characterized by left ventricular hypertrophy, myocyte hypertrophy, fibre disarray and interstitial fibrosis. To date, over 455 mutations have been reported, targeting different genes encoding proteins of myocardial sarcomere, proteins of the z-disc and of the intercalated discs. Pathogenic mutations detected in the ?-myosin heavy chain, myosin-binding protein C, troponin T and troponin I genes account for about 70% of the total.
The aim of this study is set-up a cost-effective, rapid and efficient method DHPLC-based for mutation screening in patients with hypertrophic cardiomyopathy. The protocol involve PCR amplification of exons or exon segments, denaturing high performance liquid chromatography of amplicons and direct sequencing.
Coding sequences (exons) of MYH7, MYBPC3, TNNT2 and TNNI3 genes have been screened for mutations in a series of 82 HCM patients (43 index cases and 39 isolated cases). Twenty-one mutations were identified in 24 patients.
The efficiency of the protocol was tested by analyzing DNA of 12 patients both by DHPLC and by HCM re-sequencing DNAchip. No additional variations were detected by DNAchip, if compared with those detected by DHPLC.
DHPLC analysis appears as a high-throughput, sensitive and specific method for mutation detection in patients with hypertrophic cardiomyopathy

Abstract (italian)

La cardiomiopatia ipertrofica (CMI) è una patologia del miocardio caratterizzata da ispessimento del setto interventricolare e del ventricolo sinistro, anomalo orientamento delle fibre miocardiche (disarray) e fibrosi interstiziale. La patologia viene ereditata come carattere autosomico dominante, la sua frequenza nella popolazione è di circa lo 0.2% ed è considerata la principale causa di morte improvvisa soprattutto nei giovani.
Attualmente sono note più di 455 mutazioni causative, distribuite in geni diversi che codificano proteine del sarcomero, dei dischi z o dei dischi intercalari. Le mutazioni patogene finora riportate nei geni MYH7, MYBPC3, TNNT2 e TNNI3 rappresentano circa il 70% del totale.
Il presente studio ha messo a punto un protocollo di screening relativamente rapido e poco costoso per la ricerca di mutazioni in tali geni. Il nuovo protocollo, che implica l’amplificazione PCR degli esoni, o di loro segmenti, dei geni considerati e la successiva analisi mediante DHPLC e/o sequenziamento diretto, è stato utilizzato per individuare mutazioni nelle regioni codificanti dei quattro geni in questione, in 82 soggetti affetti da cardiomiopatia ipertrofica, 43 casi indice e 39 casi isolati. Sono state individuate in tutto 21 mutazioni in 24 pazienti.
Per valutare l’efficacia del nuovo protocollo, il DNA di 12 degli 82 pazienti è stato analizzato anche mediante chip a DNA recentemente sviluppati da Fokstuen S et al. (2008). In nessuno dei DNA analizzati mediante DNA chip sono state individuate variazioni diverse da quelle identificate mediante il metodo proposto da questo studio.

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EPrint type:Ph.D. thesis
Tutor:Danieli, Gian Antonio
Ph.D. course:Ciclo 21 > Scuole per il 21simo ciclo > BIOSCIENZE > GENETICA E BIOLOGIA MOLECOLARE DELLO SVILUPPO
Data di deposito della tesi:29 January 2009
Anno di Pubblicazione:January 2009
Key Words:Cardiomiopatia Ipertrofica, DHPLC. DNAchip
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/18 Genetica
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:1682
Depositato il:29 Jan 2009
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