A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction
De novo heterozygous variants in 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 c.374G > A (p.Cys125Tyr) was identified via exome sequencing in a patient with DEE. Relative to...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2024-01, Vol.121 (3), p.e2307776121 |
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Sprache: | eng |
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Zusammenfassung: | De novo heterozygous variants in
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
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. |
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ISSN: | 0027-8424 1091-6490 1091-6490 |
DOI: | 10.1073/pnas.2307776121 |