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 keystone 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 reveal pore “turret arch” bonding as a KCNQ structural novelty 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 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 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
OpenAlex ID: W4392736162