Becker F , Reid CA , Hallmann K , Tae HS , Phillips AM , Teodorescu G , Weber YG , Kleefuss-Lie A , Elger C , Perez-Reyes E , Petrou S , Kunz WS , Lerche H , Maljevic S .

             regulation of neuronal action potential

           EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 6; ECA6
           DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 24; DEE24

	Figure 1. Pedigrees of the two GGE families. (A) Pedigree of Family 1 showing a complete cosegregation of the CACNA1H variant (orange) with the GGE phenotype and the inheritance pattern of the HCN4 variant (blue). (B) Pedigree of Family 2 in which the second HCN4 mutation p.E153G was identified in a single patient; EGMA, epilepsy with grand mal seizures on awakening; TLE, temporal lobe epilepsy; FS, febrile seizures; CAE, childhood absence epilepsy; EGTCS, epilepsy with generalized tonic‐clonic seizures.
	Figure 2. Conservation and localization of affected amino acids. (A) Alignment of protein sequences showing the conservation of affected amino acids in Cav3.2 (encoded by CACNA1H) and HCN4 proteins among different species. (B) Predicted localization of detected variants within the Cav3.2 and HCN4 channel proteins.
	Figure 3. Functional analysis of the CACNA1H variant in tsA201 cells. (A) Whole cell currents of WT Cav3.2 and G1158S channels elicited by depolarizing the membrane between −70 mV and 70 mV in 5‐mV steps from a holding potential of −90 mV. (B) Current density for the Cav3.2 WT and G1158S mutant channels at different potentials. (C) Steady‐state activation and inactivation for Cav3.2 WT and G1158S mutant channels obtained by standard protocols using a holding potential of −90 mV. Recordings were performed with Ca2+ as the charge carrier. Parameters for activation were as follows: WT – V0.5 = −41.4 ± 0.8 mV, k = −6.7 ± 0.3 mV (n = 13); G1158S – V0.5 = −40.8 ± 0.8 mV, k −1.3 ± 0.3 (n = 10). For the inactivation (inset), parameters were: WT – V0.5 = −69.2 ± 1.1 mV, k = 4.3 ± 0.2 mV (n = 11); G1158S – V0.5 = −64.1 ± 1.1 mV, k = −4.4 ± 0.1 (n = 7), **p < 0.01, unpaired t test. (D) Recovery from inactivation for Cav3.2 WT and G1158S mutant channels. Curves represent monoexponential fits to the averaged data (n = 4–12). Inset: mean time constant for recovery from inactivation for Cav3.2 WT and G1158S mutant, obtained from monoexponential fits to the normalized current recovery curve (n = 4–12, n.s. = not significant).
	Figure 4. Electrophysiological characterization of HCN4 epilepsy variants. (A) Steady‐state (left) and tail (right) currents from oocytes expressing HCN4 WT and E153G and P1117L epilepsy variants. Vertical scale bar represents 1 μA. (B) Average tail current–voltage (I–V) relationship of WT (n = 21), E153G (n = 19), and P1117L (n = 30) channels. (C) Activation curve constructed from average normalized tail currents and fit with the Boltzmann equation for HCN4 WT and E153G and P1117L variants. (D) Bar graph of the average half‐activation voltage (V0.5) for each situation.*p < 0.05, one‐way ANOVA.

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