Extended Data Fig. 2: INa,L regulation by the FHF2-3 splice variants.
a, Schematic shows various FHF2 splice variants generated by alternate start sites. Conserved exons that encode the core domain are shown in red boxes labeled E2 to E5. b-e, Exemplar recordings of LQTS3-linked ΔKPQ mutant heterologously expressed in HEK293 cells in the presence of various FHF2 splice variants. f-i, Exemplar recordings of IQ/AA mutant in the presence of FHF2 splice variants. j, Bar graph summarizes changes in INa,L quantified as Rpersist upon co-expression of FHF splice variants. FHF2S, and FHF2VY yielded a partial reduction in INa,L for both the IQ/AA and the ΔKPQ mutant, while FHF2V and FHF2U resulted in no change. Data presented as mean ± SEM. For ΔKPQ mutant, + FHF2U, n = 10 cells (561 sweeps); + FHF2V, n = 10 cells (549 sweeps); +FHF2Y, n = 9 cells (512 sweeps); and + FHF2VY, n = 9 cells (499 sweeps). For IQ/AA mutant, + FHF2U, n = 9 cells (547 sweeps); + FHF2V, n = 10 cells (807 sweeps); + FHF2Y, n = 10 cells (564 sweeps); + FHF2VY, n = 9 cells (547 sweeps). Statistical Analysis, Kruskal-Wallis test followed by Dunn’s Multiple comparisons test, ***p < 0.001;**p = 0.026(ΔKPQ + FHF2Y) and *p = 0.039(ΔKPQ + FHF2VY), *p = 0.034(IQ/AA + FHF2S) and *p = 0.011 (IQ/AA + FHF2VY) when compared to no FHF control of each mutant channel. k, Exemplar multichannel recording from recombinant NaV1.5 wild-type in HEK293 cells shown minimal late channel openings in the presence of FHF3A. Population data is shown in Fig. 2m. l, Exemplar recordings show a partial reduction in late channel openings for NaV1.5 IQ/AA mutant channel in the presence of FHF3A. Population data are shown in Fig. 2m.
