KCNQ2 Loss-of-Function variants disrupt neuronal maturation via early hyperexcitability followed by maladaptive network remodeling
Year: 2025
Type: preprint
Abstract: Loss-of-function (LOF) variants in the potassium channel subunit KCNQ2 cause a spectrum of neonatal epilepsies from self-limiting familial neonatal epilepsy (SeLFNE) to severe developmental and epileptic encephalopathy (DEE). To dissect the developmental consequences of KCNQ2 LOF, we conducted a longitudinal and multimodal comparative analysis in a human neuronal model generated from patients with KCNQ2 -DEE and KCNQ2 -SeLFNE. KCNQ2 -LOF induced a biphasic network dysfunction, with early Kv7-driven hyperexcitability rescued by acute Retigabine (RTG) treatment, followed by maladaptive remodeling in the opposite direction. Transcriptomic analysis mirrored this biphasic dynamic trajectory, revealing an initial upregulation followed by a subsequent downregulation of synaptic genes. Structural analysis showed a steeper decline in presynaptic density alongside a distal shift in the axon initial segment (AIS) throughout maturation, and impaired AIS plasticity at later stages. Overall, KCNQ2-LOF disrupts human neuronal maturation through dynamic, biphasic changes in function, gene expression and structure, offering insights into disease mechanisms and therapeutic options.
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Allele-specific silencing of mutant KCNQ2 as a targeted treatment for KCNQ2 encephalopathy: an in vitro proof of concept study, G1893116736, Flanders BioImaging: Leading Imaging Application Integrated Service and Enablement (FBI-LIAISE), Increasing diagnostic yield in genetic childhood onset epilepsies through advanced multi-omics methods and improving mechanistic insights through the study of microglia-containing brain organoids, Interactive and intelligent cellomics platform, Mutant allele silencing and novel potassium channel openers as targeted treatment strategies for KCNQ2 encephalopathy: validation in induced pluripotent stem cell derived neuronal cultures., The silence of the mutant: towards a targeted therapy for KCNQ2-encephalopathy., Nuclear envelope stress in laminopathy patient-derived cardiomyocytes (NStrC)
OpenAlex ID: W4412626071