KV7.2 channel dysfunction delays neuronal maturation and undermines early network development in a hiPSC model of KCNQ2-DEE
Year: 2025
Type: article
Abstract: Background KCNQ2 , encoding K V 7.2 ion channels, has emerged as one of the prominent genes causing early onset seizures with developmental delay ( KCNQ2 developmental and epileptic encephalopathy; KCNQ2 -DEE). KCNQ2 de novo loss-of-function (LOF) and associated neuronal hyperexcitability have been accepted as mechanisms contributing to seizures. To investigate the developmental impact of KCNQ2 LOF, we generated patient iPSC-derived models for two previously reported de novo variants, p.(Arg325Gly) and p.(Gly315Arg), linked to severe congenital DEE. Methods Functional investigation of the two variants was initially performed in Xenopus laevis oocyte system. Patient-derived iPSC lines were differentiated using NGN2- and embryoid body-based protocols yielding neurons roughly corresponding to mid- and mid-late gestational stages, respectively. K V 7- mediated M-current, passive neuronal properties, action potential generation and spontaneous oscillatory network activities were analysed with whole-cell patch clamping. Findings Studied KCNQ2 variants showed LOF with a dominant-negative effect in the heterologous system. Reduced M-currents in patient iPSC-derived neurons corroborated a LOF as the main pathomechanism. Interestingly, this led to the reduced neuronal firing of the early neurons and to a disruption of complex oscillatory activity, with significantly reduced duration and amplitude of these events in patient iPSC-derived neurons. Interpretation We provide experimental evidence for changing roles of the M-current throughout development and place disease variant-mediated M-current reduction in the context of the neuronal maturation in the prenatal brain. Based on the reduced neuronal firing and disrupted oscillatory activity seen in patient iPSC-derived neurons, we propose that a delayed/impaired maturation of neuronal and network properties underlies KCNQ -DEE caused by LOF variants.
Source: Neurobiology of Disease
Institutions: Universitätsklinikum Tübingen, Hertie Institute for Clinical Brain Research, University of Tübingen, Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, The University of Melbourne, Florey Institute of Neuroscience and Mental Health, University of Antwerp, Antwerp University Hospital, VIB-UAntwerp Center for Molecular Neurology, University Children's Hospital Tübingen
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,180
Awards: Verbundprojekt: Deutsches Netzwerk für neurologische und ophthalmologische Ionenkanalerkrankungen (IonNeurONet): TP 1: Koordination und Management, TP 5: Pathophysiologie der neuronalen Kv7.2 Kanalopathien, TP 6: Mechanismen der gestörten Oberflächenexpression in retinalen Kanalopathien, G403072156, TreatKCNQ - Gezielte Behandlung von KCNQ-Enzephalopathien: Retigabin-Analoga, Wirkstoffrepurposing und allelspezifischer Knockdown. Teilvorhaben: Validierung von Retigabin-Analoga und Repurposed Compounds in primären Mausneuron- und humanen Hirnschnitt Kulturen, G5541131645, Treat-ION - Neue Therapien für neurologische Ionenkanal- und Transporterstörungen - Untersuchung der Pathophysiologie und Therapie für ausgewählte Ataxien, hemiplegische Migräne und Anfälle sowie an iPSC abgeleiteten menschlichen Neuronen, Verbundkoordination, G7581890929
OpenAlex ID: W4414480270