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Beffagna, Giorgia and De Bortoli, Marzia and Nava, Andrea and Salamon, Michela and Lorenzon, Alessandra and Zaccolo , Manuela and Mancuso, Luisa and Sigalotti, Luca and Bauce, Barbara and Occhi, Gianluca and Basso, Cristina and Lanfranchi, Gerolamo and A Towbin, Jeffrey and Thiene, Gaetano and Danieli, Gian Antonio and Rampazzo, Alessandra (2007) Missense mutations in Desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro. [Online journal papers]

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Per gentile concessione di: http://www.biomedcentral.com/1471-2350/8/65

Abstract (english)

Background

Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC), an autosomal dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement.

We screened 54 ARVC probands for mutations in desmocollin-2 (DSC2), the only desmocollin isoform expressed in cardiac tissue.

Methods

Mutation screening was performed by denaturing high-performance liquid chromatography and direct sequencing.

To evaluate the pathogenic potentials of the DSC2 mutations detected in patients affected with ARVC, full-length wild-type and mutated cDNAs were cloned in eukaryotic expression vectors to obtain a fusion protein with green fluorescence protein (GFP); constructs were transfected in neonatal rat cardiomyocytes and in HL-1 cells.

Results

We identified two heterozygous mutations (c.304G>A (p.E102K) and c.1034T>C (p.I345T)) in two probands and in four family members. The two mutations p.E102K and p.I345T map to the N-terminal region, relevant to adhesive interactions.

In vitro functional studies demonstrated that, unlike wild-type DSC2, the two N-terminal mutants are predominantly localised in the cytoplasm.

Conclusion

The two missense mutations in the N-terminal domain affect the normal localisation of DSC2, thus suggesting the potential pathogenic effect of the reported mutations. Identification of additional DSC2 mutations associated with ARVC may result in increased diagnostic accuracy with implications for genetic counseling.


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EPrint type:Online journal papers
Anno di Pubblicazione:2007
Key Words:Mutations, ventricular cardiomyopathy.
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
Dipartimenti > Dipartimento di Biologia
Dipartimenti > pre 2012 - Dipartimento di Scienze Medico Diagnostiche e Terapie Speciali
Codice ID:1182
Depositato il:09 Dec 2008
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