GPD1L-A306del modifies sodium current in a family carrying the dysfunctional SCN5A-G1661R mutation associated with Brugada syndrome.
BrS
Brugada syndrome
GPD1L
Nav1.5
SCN5A
Sodium channel
Journal
Pflugers Archiv : European journal of physiology
ISSN: 1432-2013
Titre abrégé: Pflugers Arch
Pays: Germany
ID NLM: 0154720
Informations de publication
Date de publication:
01 Dec 2023
01 Dec 2023
Historique:
received:
26
04
2023
accepted:
08
11
2023
revised:
06
11
2023
medline:
1
12
2023
pubmed:
1
12
2023
entrez:
30
11
2023
Statut:
aheadofprint
Résumé
Loss-of-function variants of SCN5A, encoding the sodium channel alpha subunit Nav1.5 are associated with high phenotypic variability and multiple cardiac presentations, while underlying mechanisms are incompletely understood. Here we investigated a family with individuals affected by Brugada Syndrome (BrS) of different severity and aimed to unravel the underlying genetic and electrophysiological basis.Next-generation sequencing was used to identify the genetic variants carried by family members. The index patient, who was severely affected by arrhythmogenic BrS, carried previously uncharacterized variants of Nav1.5 (SCN5A-G1661R) and glycerol-3-phosphate dehydrogenase-1-like protein (GPD1L-A306del) in a double heterozygous conformation. Family members exclusively carrying SCN5A-G1661R showed asymptomatic Brugada ECG patterns, while another patient solely carrying GPD1L-A306del lacked any clinical phenotype.To assess functional mechanisms, Nav1.5 channels were transiently expressed in HEK-293 cells in the presence and absence of GPD1L. Whole-cell patch-clamp recordings revealed loss of sodium currents after homozygous expression of SCN5A-G1661R, and reduction of current amplitude to ~ 50% in cells transfected with equal amounts of wildtype and mutant Nav1.5. Co-expression of wildtype Nav1.5 and GPD1L showed a trend towards increased sodium current amplitudes and a hyperpolarizing shift in steady-state activation and -inactivation compared to sole SCN5A expression. Application of the GPD1L-A306del variant shifted steady-state activation to more hyperpolarized and inactivation to more depolarized potentials.In conclusion, SCN5A-G1661R produces dysfunctional channels and associates with BrS. SCN5A mediated currents are modulated by co-expression of GDP1L and this interaction is altered by mutations in both proteins. Thus, additive genetic burden may aggravate disease severity, explaining higher arrhythmogenicity in double mutation carriers.
Identifiants
pubmed: 38036776
doi: 10.1007/s00424-023-02882-0
pii: 10.1007/s00424-023-02882-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Max-Planck-Gesellschaft
ID : TANDEM project
Organisme : Max-Planck-Gesellschaft
ID : TANDEM project
Organisme : Deutsche Forschungsgemeinschaft
ID : SCHW 1611/1-1
Informations de copyright
© 2023. The Author(s).
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