Park J , Koko M , Hedrich UBS , Hermann A , Cremer K , Haberlandt E , Grimmel M , Alhaddad B , Beck-Woedl S , Harrer M , Karall D , Kingelhoefer L , Tzschach A , Matthies LC , Strom TM , Ringelstein EB , Sturm M , Engels H , Wolff M , Lerche H , Haack TB .

FOR-2715 Deutsche Forschungsgemeinschaft, University of Tuebingen, FKZ 01GM1907A Bundesministerium für Bildung und Forschung, FKZ 01ZX1405C Bundesministerium für Bildung und Forschung, # intramural fortüne program, 2435-0-0 intramural fortüne program

                intellectual disability
                epilepsy
                Unverricht-Lundborg syndrome
                episodic ataxia

           EPILEPSY, PROGRESSIVE MYOCLONIC 7; EPM7

Figure 1. (A) Pedigrees of the five unrelated affected individuals (closed symbols) with de novo KCNC1 variants and status of healthy family members (open symbols). wt indicates for wild type. (B) Graphical illustration of the KV3.1 channel demonstrates the domain structures. The positions of the identified variants (Cys208Tyr, Thr399Met, Ala421Val) and the previously published variants (Arg320His and Arg339*) are highlighted with stars. The plus sign illustrates the positively charged arginine in the voltage‐sensing S4 segment.21 (C) Amino acid sequences across different species indicate that the variants are localized in highly conserved regions. (D) Images of patient 2 at 11 years of age show hypertelorism, long palpebral fissures, broad nose, large ears, diastema, small chin, and sandal gap. The hands of patient 2 do not have any dysmorphic features.

Figure 2. Functional consequences of the identified KCNC1 variants. (A) Representative traces of KV3.1 currents recorded in Xenopus laevis oocytes expressing the wild type (WT) and the single‐site variants (Cys208Tyr, Thr399Met, Ala421Val) in response to the voltage steps from − 60 mV to + 60 mV. (B) Relative current amplitudes of oocytes injected with the WT (n = 23), Cys208Tyr (n = 8), Thr399Met (n = 14), and Ala421Val (n = 8) mutant channels (Dunn’s test, P < 0.05). Mean current amplitudes of currents elicited by a + 40 mV voltage step were analyzed between 0.4 and 0.5 msec and normalized to the mean value of WT channels recorded on the same day. (C) Representative current traces recorded in oocytes that were coinjected with WT cRNA and either water or a mutant cRNA in a 1:1 ratio. (D) Relative current amplitudes recorded from oocytes coexpressing WT and mutant channels (WT + H2O (n = 36), WT + Cys208Tyr (n = 8), WT + Thr399Met (n = 6), WT + Ala421Val (n = 27)) were normalized to the mean current amplitude of oocytes coinjected with the WT channel and water recorded on the same day (Dunn's test, P < 0.05). (E) Mean voltage‐dependent activation of KV3.1 channel for WT (n = 20), WT + Cys208Tyr (n = 5) and WT + Ala421Val (n = 10) channels. Lines illustrate Boltzmann Function fit to the data points. The activation curve of WT + Ala421Val channels showed a significant shift to more hyperpolarized potentials in comparison to WT channels alone. All data are shown as means ± SEM. The following symbols were used for statistical differences: * P < 0.05, ** P < 0.01 and ns for not significant.

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