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Functional Characterisation of the Rare SCN5A p.E1225K Variant, Segregating in a Brugada Syndrome Familial Case, in Human Cardiomyocytes from Pluripotent Stem Cells

Articolo
Data di Pubblicazione:
2023
Citazione:
Functional Characterisation of the Rare SCN5A p.E1225K Variant, Segregating in a Brugada Syndrome Familial Case, in Human Cardiomyocytes from Pluripotent Stem Cells / Salvarani, Nicolò; Peretto, Giovanni; Silvia, Crasto; Villatore, Andrea; Thairi, Cecilia; Santoni, Anna; Galli, Camilla; Carrera, Paola; Sala, Simone; Benedetti, Sara; Di Pasquale, Elisa; Di Resta, Chiara. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 24:11(2023), p. 9548. [10.3390/ijms24119548]
Abstract:
Brugada syndrome (BrS) is an inherited autosomal dominant cardiac channelopathy. Pathogenic rare mutations in the SCN5A gene, encoding the alpha-subunit of the voltage-dependent cardiac Na+ channel protein (Nav1.5), are identified in 20% of BrS patients, affecting the correct function of the channel. To date, even though hundreds of SCN5A variants have been associated with BrS, the underlying pathogenic mechanisms are still unclear in most cases. Therefore, the functional characterization of the SCN5A BrS rare variants still represents a major hurdle and is fundamental to confirming their pathogenic effect. Human cardiomyocytes (CMs) differentiated from pluripotent stem cells (PSCs) have been extensively demonstrated to be reliable platforms for investigating cardiac diseases, being able to recapitulate specific traits of disease, including arrhythmic events and conduction abnormalities. Based on this, in this study, we performed a functional analysis of the BrS familial rare variant NM_198056.2:c.3673G>A (NP_932173.1:p.Glu1225Lys), which has been never functionally characterized before in a cardiac-relevant context, as the human cardiomyocyte. Using a specific lentiviral vector encoding a GFP-tagged SCN5A gene carrying the specific c.3673G>A variant and CMs differentiated from control PSCs (PSC-CMs), we demonstrated an impairment of the mutated Nav1.5, thus suggesting the pathogenicity of the rare BrS detected variant. More broadly, our work supports the application of PSC-CMs for the assessment of the pathogenicity of gene variants, the identification of which is increasing exponentially due to the advances in next-generation sequencing methods and their massive use in genetic testing.
Tipologia CRIS:
1.1 Articolo in rivista
Elenco autori:
Salvarani, Nicolò; Peretto, Giovanni; Silvia, Crasto; Villatore, Andrea; Thairi, Cecilia; Santoni, Anna; Galli, Camilla; Carrera, Paola; Sala, Simone; Benedetti, Sara; Di Pasquale, Elisa; Di Resta, Chiara
Autori di Ateneo:
DI RESTA CHIARA
Link alla scheda completa:
https://iris.unisr.it/handle/20.500.11768/146919
Link al Full Text:
https://iris.unisr.it//retrieve/handle/20.500.11768/146919/153684/2023_Salvarani%20et%20al.,%20IJMS.pdf
Pubblicato in:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Journal
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URL

https://www.mdpi.com/1422-0067/24/11/9548
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