Maghera J, Li J, Lamothe SM, Braun M, Appendino JP, Au PYB, Kurata HT.

                epilepsy

	Figure 1. Inheritance of Kv7.2 and Kv7.3 mutations associated with epilepsy. A, Mutations in Kv7.2 or Kv7.3 associated with a documented case of epilepsy (compiled from ClinVar or RIKEE databases) are highlighted on molecular models of each channel. Mutations are color coded based on severity (green = BFNE, red = epileptic encephalopathy or other severe outcomes). Mutations that do not map to structural elements defined in the KCNQ1 cryo‐EM structure have been omitted (VSD, voltage‐sensing domain, SF, selectivity filter, CaM, Calmodulin). B, Pattern of inheritance of a neonatal seizure phenotype in a family carrying the Kv7.3[T313I] mutation. Upper, sequence alignment of the reference KCNQ3 gene and Kv7.3 protein in relation to the proband. The identified mutation [T313I] is highlighted in bold type. Lower, pedigree for the family characterized in our study with filled symbols indicating affected individuals
	Figure 2. v7.3[T313I] abolishes Kv7.3 function. A, Molecular model of essential intersubunit hydrogen bond between conserved residues T313 and Y319 located in the selectivity signature sequence. B, Two‐electrode voltage‐clamp recordings from Xenopus laevis oocytes expressing Kv7.3[A315T] and Kv7.3[A315T][T313I]. Oocytes were held at −80 mV and depolarized for 1.5s to voltages between −140 mV and +40 mV (in 10‐mV steps) followed by repolarization to −20 mV test pulse. Current amplitudes at +20 mV of Kv7.3 [A315T] and Kv7.3[A315T] [T313I] were compared using a student’s t test (* indicates P<0.05 relative to A315T alone)
	Figure 3. Co‐expression with Kv7.2 and Kv7.3[T313I] reduces heteromeric channel function with no effect on gating. A, Two‐electrode voltage‐clamp sample traces from oocytes expressing various combinations of Kv7.2 and Kv7.3 (injected with a total of 50 ng of mRNA per group). The voltage step protocol is the same as Figure 2B. B, Current amplitudes after a 1.5 s + 20 mV voltage step. Current magnitudes were compared using one‐way ANOVA, followed by Tukey’s post hoc test (* indicates P < 0.05). C, Conductance‐voltage relationships were collected using the protocol in panel (A), using tail current magnitudes (−20 mV) to assess the extent of channel opening during the conditioning step. Fitted gating parameters were (mean ± S.E.M.): for Kv7.2 + Kv7.3 +[T313I], k = 9.4 ± 0.3 mV, V1/2 = −30 ± 1 mV; for Kv7.2 + [T313I], k = 9.1 ± 0.3 mV, V1/2 = −35.1 ± 0.5 mV; for Kv7.2 + Kv7.3, k = 10.2 ± 0.3 mV, V1/2 = −34.2 ± 0.3 mV; for Kv7.2 homomers, k = 9.2 ± 0.2 mV, V1/2 = −34.2 ± 0.6 mV. No significant differences in gating parameters were detected
	Figure 4. Reduced ICA‐069673 sensitivity of Kv7.2/Kv7.3[T313I] heteromeric channels. A, Example currents of two‐electrode voltage‐clamp recordings. Oocytes were depolarized to +20 mV and repolarized for 12 s in a step‐down manner (−20 mV per sweep), followed by another +20 mV depolarizing pulse to determine instantaneous current at −100 mV. Currents within the dashed box are illustrated on an expanded time scale in the right panels, showing the assessment of instantaneous current levels in different experimental conditions. B, Fractional instantaneous current after incubation with 100 μmol/L ICA‐069673 was measured as indicated by the arrows in panel (A), data are shown as mean ± SEM. C, Fractional instantaneous current (repolarization voltage of −100 mV) for various combinations of Kv7.2, Kv7.3, and Kv7.3[T313I], shown on a cell‐by‐cell basis (Kruskal‐Wallis one‐way ANOVA on ranks, * indicates P < 0.05 relative to Kv7.2 homomeric channels)
	Figure 5. Variable outcomes of homologous selectivity filter mutations in Kv7.2 and Kv7.3. A, Current magnitude was measured at +20 mV in Xenopus oocytes injected with Kv7.2 + Kv7.3, or various combinations of channel mutants and their wild‐type counterpart, as indicated. Currents were recording 48‐56 h after injection (n = 10 per condition, one‐way ANOVA on ranks and Tukey post hoc test, # indicates P < 0.05 relative to Kv7.2/Kv7.3, * indicates P < 0.05 relative to Kv7.2/Kv7.3[T313I]). B, Instantaneous tail current magnitudes were recorded as described in Figure 4 in the presence of 100 μmol/L ICA‐069673, for all possible combinations of injected channels (note that Kv7.3 + Kv7.2[T274I] did not yield current sizes that could be confidently assessed or analyzed)

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