The Nav1.5 variant G213D found in patients with MEPPC is associated with increased window current and gating pore current

enetic variants in the SCN5A gene have been linked to the multifocal ectopic Purkinje-related premature contractions (MEPPC) syndrome, characterized by frequent premature contractions and dilated cardiomyopathy (DCM). The link between MEPPC and SCN5A variants is not fully understood but an increased sodium current, either through increased window current or a gating pore current appear to play a role. In a large Danish family it was found that an MEPPC-like phenotype co-segregated with the genetic variant c.638G>A in SCN5A resulting in p.Gly213Asp (G213D).

For characterization, G213D was inserted in human induced pluripotent stem cells (hiPSCs) using CRISPR/Cas9 gene editing. Wildtype (WT) and G213D hiPSCs were differentiated into cardiomyocytes. Sodium currents (INa) were measured by voltage clamp and action potentials were recorded from stem cell-derived cardiomyocytes.

The half-maximal of INa activation of G213D was significantly more negative compared to WT, while the half-maximal of steady-state inactivation was significantly shifted towards more positive potentials. Both findings suggest a gain-of-function. In Xenopus laevis oocytes, a gating pore current was found.

In conclusion, G213D is a gain-of-function variant associated with the MEPPC syndrome. It leads to an increased window current and induces a gating pore current.