Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy
Year: 2024
Type: preprint
Abstract: KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.
Source: eLife
Authors: Timothy J Abreo, Emma C Thompson, Anuraag Madabushi, Heun Soh, Nissi Varghese, Carlos G Vanoye, Kristen Springer, Kristen L Park, Jim Johnson, Scotty Sims, Zhigang Ji, Ana G Chavez, Miranda J Jankovic, Bereket Habte, Aamir R Zuberi, Cathleen Lutz, Zhao Wang, Vaishnav Krishnan, Lisa Dudler, Stephanie Einsele-Scholz, Jeffrey L Noebels, Alfred L George, Atul Maheshwari, Anastasios V Tzingounis, Edward C Cooper
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: Welch Foundation, American Epilepsy Society, Citizens United for Research in Epilepsy, Cancer Prevention and Research Institute of Texas, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: UNRAVELLING THE MECHANISMS OF EPILEPSY-DEPRESSION COMORBIDITY IN A GENETIC MOUSE MODEL OF TEMPORAL LOBE EPILEPSY, Cellular and Network Basis of Anti-Epileptic Drug Response, New Capabilities for Cancer Research in the TMC CryoEM Cores, The Jackson Laboratory Center for Precision Genetics: From New Models to Novel Therapeutics, KCNQ2/3 channels in neonatal-onset epilepsy and encephalopathy, G3577765666, Channelopathy-Associated Epilepsy Research Center, The Development of Inhibitory Networks Regulating Sustained Attention, G5486484290, Baylor College of Medicine Intellectual and Developmental Disabilities Research Center, KCNQ2/3 channels and interneuron physiology, Investigation of the Cellular and Molecular Mechanisms of Thrombocyte Integrin Signaling, Excitability and Plasticity of Developing Epileptic Brain, Molecular mechanism of Androgen Receptor mediated transcription, Cancer Center Support (CORE) Grant
OpenAlex ID: W4401906102