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A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction
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2024 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 121, no 3Article in journal (Refereed) Published
Abstract [en]

De novo heterozygous variants in KCNC2 encoding the voltage-gated potassium (K+) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de novo variant in KCNC2 c.374G > A (p.Cys125Tyr) was identified via exome sequencing in a patient with DEE. Relative to wild-type Kv3.2, Kv3.2-p.Cys125Tyr induces K+ currents exhibiting a large hyperpolarizing shift in the voltage dependence of activation, accelerated activation, and delayed deactivation consistent with a relative stabilization of the open conformation, along with increased current density. Leveraging the cryogenic electron microscopy (cryo-EM) structure of Kv3.1, molecular dynamic simulations suggest that a strong π-π stacking interaction between the variant Tyr125 and Tyr156 in the α-6 helix of the T1 domain promotes a relative stabilization of the open conformation of the channel, which underlies the observed gain of function. A multicompartment computational model of a Kv3-expressing parvalbumin-positive cerebral cortex fast-spiking γ-aminobutyric acidergic (GABAergic) interneuron (PV-IN) demonstrates how the Kv3.2-Cys125Tyr variant impairs neuronal excitability and dysregulates inhibition in cerebral cortex circuits to explain the resulting epilepsy.

Place, publisher, year, edition, pages
Proceedings of the National Academy of Sciences , 2024. Vol. 121, no 3
Keywords [en]
epilepsy, KCNC2, Kv3.2, neurogenetics, potassium channels
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:kth:diva-342641DOI: 10.1073/pnas.2307776121PubMedID: 38194456Scopus ID: 2-s2.0-85182094409OAI: oai:DiVA.org:kth-342641DiVA, id: diva2:1831235
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QC 20240125

Available from: 2024-01-25 Created: 2024-01-25 Last updated: 2024-01-25Bibliographically approved

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Delemotte, Lucie

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