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. 2022 Aug 24;83:104234. doi: 10.1016/j.ebiom.2022.104234

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© 2022 The Author(s)

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMC Copyright notice

Electrophysiological analysis of FGF12 variants on Na_V1.2. Functional analysis of the effect of 2 FGF12 missense variants (S8P and G112S) and two FGF12 CNVs (duplication 1L and duplication 2L) on Na_V1.2 compared to WTA. Statistically significant effects for each condition are indicated by coloured asterisks.

a. Representative traces of Na_V1.2 currents in ND7/23 cells expressing Na_V1.2 with FGF12 WTA or the FGF12 variants, respectively, in response to voltage steps from -80 to +35 mV in 5 mV steps.

b. Mean Current amplitudes of analysed ND7/23 cells injected with Na_V1.2 with WTA (n=13; 5 transfections), S8P (n=11; 6 transfections; p = 0·2), G112S (n=11; 4 transfections; p = 0·3), duplication 1L (n=11; 4 transfections; p = 0·4) or duplication 2L (n=12; 6 transfections; p = 0·1). None of the variants lead to a change in the current density of Na_V1.2. For the statistical analysis ANOVA on ranks with Dunn´s post hoc test was used.

c. Mean voltage-dependent fast inactivation of Na_V1.2 with FGF12 WTA (n=13; 5 transfections), G112S (n=11; 4 transfections; p (V_1/2) = 0·01), duplication 1L (n=11; 4 transfections; p (V_1/2) = 0·009) or duplication 2L (n=12; 6 transfections; p (k) = 0·006). Lines illustrate Boltzmann Function fit to the data points. G112S showed a statistically significant shift to more depolarized potentials in comparison to WTA while duplication 1L shows a hyperpolarizing shift in comparison to WTA and duplication 2L changes the slope of the fast inactivation. All data are shown as means ± SEM. For the statistical analysis ANOVA on ranks with Dunn´s post hoc test was used.

d. Time course of recovery from fast inactivation of Na_V1.2 with FGF12 WTA (n=11; 5 transfections) or FGF12 S8P (n=10; 4 transfections; p (τ2) = 0·01) determined at -100 mV. The variant S8P leads to a statistically significantly accelerated recovery of fast inactivation in comparison to WTA. Lines represent fits of biexponential functions yielding the time constants τ1 and τ2. A1 was set to 0·3. For the statistical analysis ANOVA on ranks with Dunn´s post hoc test was used.

e. Mean voltage-dependent fast inactivation time constant of Na_V1.2 FGF12 WTA (n=11; 5 transfections) or G112S (n=11; 4 transfections; p = 0·009). G112S show a statistically significantly slowed fast inactivation in comparison to WTA. All data are shown as means ± SEM. For the statistical analysis one-way ANOVA with Holm-Sidak´s post hoc test was used.

f. Mean voltage-dependent slow inactivation of Na_V1.2 with FGF12 WTA (n=10; 5 transfections) or FGF12 duplication 1L (n=10; 4 transfections; p (k)= 0·04). Lines illustrate Boltzmann Function fit to the data points. FGF12 duplication 1L shows a change in the slope of the slow inactivation in comparison to Na_V1.2 with FGF12 WTA. All data are shown as means ± SEM. All values of electrophysiological results, numbers and p-values are listed in Table 2 and are shown as means with the 95% confidence interval. For the statistical analysis of the slow inactivation one-way ANOVA with Holm-Sidak´s post hoc test was used.