AUTHOR=Nakajima Tadashi , Tamura Shuntaro , Kawabata-Iwakawa Reika , Itoh Hideki , Hasegawa Hiroshi , Kobari Takashi , Harasawa Shun , Sekine Akiko , Nishiyama Masahiko , Kurabayashi Masahiko , Imoto Keiji , Kaneko Yoshiaki , Nakatani Yosuke , Horie Minoru , Ishii Hideki 

TITLE=Novel KCNQ1 Q234K variant, identified in patients with long QT syndrome and epileptiform activity, induces both gain- and loss-of-function of slowly activating delayed rectifier potassium currents

JOURNAL=Frontiers in Physiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2024.1401822

DOI=10.3389/fphys.2024.1401822

ISSN=1664-042X

ABSTRACT=<sec><title>Introduction</title><p>KCNQ1 and KCNE1 form slowly activating delayed rectifier potassium currents (I<sub>Ks</sub>). Loss-of-function of I<sub>Ks</sub> by <italic>KCNQ1</italic> variants causes type-1 long QT syndrome (LQTS). Also, some <italic>KCNQ1</italic> variants are reported to cause epilepsy. Segment 4 (S4) of voltage-gated potassium channels has several positively-charged amino acids that are periodically aligned, and acts as a voltage-sensor. Intriguingly, KCNQ1 has a neutral-charge glutamine at the third position (Q3) in the S4 (Q234 position in KCNQ1), which suggests that the Q3 (Q234) may play an important role in the gating properties of I<sub>Ks</sub>. We identified a novel <italic>KCNQ1</italic> Q234K (substituted for a positively-charged lysine) variant in patients (a girl and her mother) with LQTS and epileptiform activity on electroencephalogram. The mother had been diagnosed with epilepsy. Therefore, we sought to elucidate the effects of the <italic>KCNQ1</italic> Q234K on gating properties of I<sub>Ks</sub>.</p></sec><sec><title>Methods</title><p>Wild-type (WT)-KCNQ1 and/or Q234K-KCNQ1 were transiently expressed in tsA201-cells with KCNE1 (E1) (WT + E1-channels, Q234K + E1-channels, and WT + Q234K + E1-channels), and membrane currents were recorded using whole-cell patch-clamp techniques.</p></sec><sec><title>Results</title><p>At 8-s depolarization, current density (CD) of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly larger than the WT + E1-channels (WT + E1: 701 ± 59 pA/pF; Q234K + E1: 912 ± 50 pA/pF, <italic>p</italic> &lt; 0.01; WT + Q234K + E1: 867 ± 48 pA/pF, <italic>p</italic> &lt; 0.05). Voltage dependence of activation (VDA) of the Q234K + E1-channels or WT + Q234K + E1-channels was slightly but significantly shifted to depolarizing potentials in comparison to the WT + E1-channels ([V<sub>1/2</sub>] WT + E1: 25.6 ± 2.6 mV; Q234K + E1: 31.8 ± 1.7 mV, <italic>p</italic> &lt; 0.05; WT + Q234K + E1: 32.3 ± 1.9 mV, <italic>p</italic> &lt; 0.05). Activation rate of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly delayed in comparison to the WT + E1-channels ([half activation time] WT + E1: 664 ± 37 ms; Q234K + E1: 1,417 ± 60 ms, <italic>p</italic> &lt; 0.01; WT + Q234K + E1: 1,177 ± 71 ms, <italic>p</italic> &lt; 0.01). At 400-ms depolarization, CD of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly decreased in comparison to the WT + E1-channels (WT + E1: 392 ± 42 pA/pF; Q234K + E1: 143 ± 12 pA/pF, <italic>p</italic> &lt; 0.01; WT + Q234K + E1: 209 ± 24 pA/pF, <italic>p</italic> &lt; 0.01) due to delayed activation rate and depolarizing shift of VDA.</p></sec><sec><title>Conclusion</title><p>The <italic>KCNQ1</italic> Q234K induced I<sub>Ks</sub> gain-of-function during long (8-s)-depolarization, while loss of-function during short (400-ms)-depolarization, which indicates that the variant causes LQTS, and raises a possibility that the variant may also cause epilepsy. Our data provide novel insights into the functional consequences of charge addition on the Q3 in the S4 of KCNQ1.</p></sec>