Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy
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 KCN...
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/91204 |
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| author | Timothy J Abreo Emma C Thompson Anuraag Madabushi Kristen L Park Heun Soh Nissi Varghese Carlos G Vanoye Kristen Springer Jim Johnson Scotty Sims Zhigang Ji Ana G Chavez Miranda J Jankovic Bereket Habte Aamir R Zuberi Cathleen M Lutz Zhao Wang Vaishnav Krishnan Lisa Dudler Stephanie Einsele-Scholz Jeffrey L Noebels Alfred L George Atul Maheshwari Anastasios Tzingounis Edward C Cooper |
| author_facet | Timothy J Abreo Emma C Thompson Anuraag Madabushi Kristen L Park Heun Soh Nissi Varghese Carlos G Vanoye Kristen Springer Jim Johnson Scotty Sims Zhigang Ji Ana G Chavez Miranda J Jankovic Bereket Habte Aamir R Zuberi Cathleen M Lutz Zhao Wang Vaishnav Krishnan Lisa Dudler Stephanie Einsele-Scholz Jeffrey L Noebels Alfred L George Atul Maheshwari Anastasios Tzingounis Edward C Cooper |
| author_sort | Timothy J Abreo |
| collection | DOAJ |
| description | 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. Kcnq2G256W/+ 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. |
| format | Article |
| id | doaj-art-98a9e6a68b4346a7b68a9bbb0cfd437d |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-98a9e6a68b4346a7b68a9bbb0cfd437d2025-01-07T12:28:21ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011310.7554/eLife.91204Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathyTimothy J Abreo0https://orcid.org/0000-0001-5675-7932Emma C Thompson1Anuraag Madabushi2Kristen L Park3https://orcid.org/0000-0001-5527-3047Heun Soh4Nissi Varghese5Carlos G Vanoye6https://orcid.org/0000-0002-4935-1122Kristen Springer7Jim Johnson8Scotty Sims9Zhigang Ji10Ana G Chavez11Miranda J Jankovic12Bereket Habte13Aamir R Zuberi14https://orcid.org/0000-0003-0252-9760Cathleen M Lutz15Zhao Wang16Vaishnav Krishnan17Lisa Dudler18Stephanie Einsele-Scholz19Jeffrey L Noebels20Alfred L George21https://orcid.org/0000-0002-3993-966XAtul Maheshwari22https://orcid.org/0000-0003-3045-7901Anastasios Tzingounis23Edward C Cooper24https://orcid.org/0000-0003-3672-8442Department of Neurology, Baylor College of Medicine, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United StatesDepartment of Neurology, Baylor College of Medicine, Houston, United StatesDepartment of Neurology, Baylor College of Medicine, Houston, United StatesDepartment of Neurology, Children’s Colorado, University of Colorado, Aurora, United States; Department of Pediatrics, Children’s Colorado, University of Colorado, Aurora, United StatesDepartment of Physiology and Neurobiology, University of Connecticut, Storrs, United StatesDepartment of Physiology and Neurobiology, University of Connecticut, Storrs, United StatesDepartment of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United StatesDepartment of Physiology and Neurobiology, University of Connecticut, Storrs, United StatesKCNQ2 Cure Alliance, Denver, United StatesKCNQ2 Cure Alliance, Denver, United StatesDepartment of Neurology, Baylor College of Medicine, Houston, United StatesDepartment of Neurology, Baylor College of Medicine, Houston, United States; Department of Neuroscience, Baylor College of Medicine, Houston, United StatesDepartment of Neurology, Baylor College of Medicine, Houston, United StatesDepartment of Neurology, Children’s Colorado, University of Colorado, Aurora, United States; Department of Pediatrics, Children’s Colorado, University of Colorado, Aurora, United StatesThe Rare Disease Translational Center & Technology Evaluation and Development, The Jackson Laboratory, Bar Harbor, United StatesThe Rare Disease Translational Center & Technology Evaluation and Development, The Jackson Laboratory, Bar Harbor, United StatesDepartment of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, United States; CryoEM Core, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United StatesDepartment of Neurology, Baylor College of Medicine, Houston, United States; Department of Neuroscience, Baylor College of Medicine, Houston, United States; Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, United StatesCenter for Human Genetics Tübingen, Tübingen, GermanyCenter for Human Genetics Tübingen, Tübingen, GermanyDepartment of Neurology, Baylor College of Medicine, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Department of Neuroscience, Baylor College of Medicine, Houston, United StatesDepartment of Neurology, Children’s Colorado, University of Colorado, Aurora, United StatesDepartment of Neurology, Baylor College of Medicine, Houston, United States; Department of Neuroscience, Baylor College of Medicine, Houston, United StatesDepartment of Physiology and Neurobiology, University of Connecticut, Storrs, United StatesDepartment of Neurology, Baylor College of Medicine, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Department of Neuroscience, Baylor College of Medicine, Houston, United StatesKCNQ2 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. Kcnq2G256W/+ 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.https://elifesciences.org/articles/91204channelopathyaxon initial segmentbrain developmentepilepsyprecision medicine |
| spellingShingle | Timothy J Abreo Emma C Thompson Anuraag Madabushi Kristen L Park Heun Soh Nissi Varghese Carlos G Vanoye Kristen Springer Jim Johnson Scotty Sims Zhigang Ji Ana G Chavez Miranda J Jankovic Bereket Habte Aamir R Zuberi Cathleen M Lutz Zhao Wang Vaishnav Krishnan Lisa Dudler Stephanie Einsele-Scholz Jeffrey L Noebels Alfred L George Atul Maheshwari Anastasios Tzingounis Edward C Cooper Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy eLife channelopathy axon initial segment brain development epilepsy precision medicine |
| title | Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy |
| title_full | Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy |
| title_fullStr | Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy |
| title_full_unstemmed | Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy |
| title_short | Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy |
| title_sort | plural molecular and cellular mechanisms of pore domain kcnq2 encephalopathy |
| topic | channelopathy axon initial segment brain development epilepsy precision medicine |
| url | https://elifesciences.org/articles/91204 |
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