Constitutive opening of the Kv7.2 pore activation gate causes <i>KCNQ2</i> -developmental encephalopathy

Pathogenic variants in <i>KCNQ2</i> encoding Kv7.2 voltage-gated potassium channel subunits cause developmental encephalopathies (<i>KCNQ2</i>-encephalopathies), both with and without epilepsy. We herein describe the clinical, in vitro, and in silico features of two encephalopathy-causing variants (A317T, L318V) in Kv7.2 affecting two consecutive residues in the S<sub>6</sub> activation gate that undergoes large structural rearrangements during pore opening; the disease-causing A356T variant in <i>KCNQ3</i>, paralogous to the A317T variant in <i>KCNQ2</i>, was also investigated. Currents through <i>KCNQ2</i> mutant channels displayed increased density, hyperpolarizing shifts in activation gating, faster activation and slower deactivation kinetics, and resistance to changes in the cellular concentrations of phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>), a critical regulator of Kv7 channel function; all these features are consistent with a strong gain-of-function effect. An increase in the probability of single-channel opening, with no change in membrane abundance or single-channel conductance, was responsible for the observed gain-of-function effects. All-atom molecular dynamics simulations revealed that the mutations widened the inner pore gate and stabilized a constitutively open channel configuration in the closed state, with minimal effects on the open conformation. Thus, mutation-induced stabilization of the inner pore gate open configuration is a molecular pathogenetic mechanism for <i>KCNQ2</i>-related encephalopathies.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-11-27
DOI
https://doi.org/10.1073/pnas.2412388121
Citations
6
Primary Topic
Ion channel regulation and function
Type
article
Field-Weighted Citation Impact
1.40

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article

Constitutive opening of the Kv7.2 pore activation gate causes KCNQ2 -developmental encephalopathy

Sarah Weckhuysen, Alessandro Berselli, Vincenzo Barrese, Francesco Miceli et al.
6 citations
Proceedings of the National Academy of Sciences
Ion channel regulation and function
1.40
article

Constitutive opening of the Kv7.2 pore activation gate causes KCNQ2 -developmental encephalopathy

Sarah Weckhuysen, Alessandro Berselli, Vincenzo Barrese, Francesco Miceli, Maria Virginia Soldovieri, Mario Nappi, Ingrid Eileen Scheffer, Luca Maragliano, Maurizio Taglialatela, Ilenio Servettini, Annie Ting Gee Chiu, Fabio Benfenati, Giulio Alberini, Agnese Roscioni
article en
6 citations

Abstract

Pathogenic variants in <i>KCNQ2</i> encoding Kv7.2 voltage-gated potassium channel subunits cause developmental encephalopathies (<i>KCNQ2</i>-encephalopathies), both with and without epilepsy. We herein describe the clinical, in vitro, and in silico features of two encephalopathy-causing variants (A317T, L318V) in Kv7.2 affecting two consecutive residues in the S<sub>6</sub> activation gate that undergoes large structural rearrangements during pore opening; the disease-causing A356T variant in <i>KCNQ3</i>, paralogous to the A317T variant in <i>KCNQ2</i>, was also investigated. Currents through <i>KCNQ2</i> mutant channels displayed increased density, hyperpolarizing shifts in activation gating, faster activation and slower deactivation kinetics, and resistance to changes in the cellular concentrations of phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>), a critical regulator of Kv7 channel function; all these features are consistent with a strong gain-of-function effect. An increase in the probability of single-channel opening, with no change in membrane abundance or single-channel conductance, was responsible for the observed gain-of-function effects. All-atom molecular dynamics simulations revealed that the mutations widened the inner pore gate and stabilized a constitutively open channel configuration in the closed state, with minimal effects on the open conformation. Thus, mutation-induced stabilization of the inner pore gate open configuration is a molecular pathogenetic mechanism for <i>KCNQ2</i>-related encephalopathies.

Proceedings of the National Academy of SciencesVol. 121(49)
Marche Polytechnic University (IT), University of Molise (IT), Royal Children's Hospital (AU), University of Antwerp (BE), The University of Melbourne (AU), Florey Institute of Neuroscience and Mental Health (AU), Italian Institute of Technology (IT), Antwerp University Hospital (BE), Ospedale Policlinico San Martino (IT), Murdoch Children's Research Institute (AU), Austin Health (AU), University of Naples Federico II (IT), University of Genoa (IT)
European Commission, Fonds Wetenschappelijk Onderzoek, Ministero della Salute, Ministero dell’Istruzione, dell’Università e della Ricerca, Istituto Italiano di Tecnologia, Ministero dell'Università e della Ricerca
Openalex Percentile: Top 18%
Ion channel regulation and function
1.40
DOIOpen Access PDFOpenAlex
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