GPD1L-A306del modifies sodium current in a family carrying the dysfunctional SCN5A-G1661R mutation associated with Brugada syndrome

• Published in: Pflügers Archiv 2024-02, Vol.476 (2), p.229-242
• Main Authors: Semino, Francesca, Darche, Fabrice F., Bruehl, Claus, Koenen, Michael, Skladny, Heyko, Katus, Hugo A., Frey, Norbert, Draguhn, Andreas, Schweizer, Patrick A.
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Cell Biology; Genetic diversity; Genetic variability; Glycerol; Glycerol-3-phosphate; Glycerol-3-phosphate dehydrogenase; Human Physiology; Ion Channels; Ion Channels, Receptors and Transporters; Molecular Medicine; Mutation; Neurosciences; Next-generation sequencing; Phenotypes; Receptors; Receptors and Transporters; Sodium; Sodium channels (voltage-gated)
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-023-02882-0

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.