{"entity": "researcher", "timestamp": "2026-07-22T17:06:39.286Z", "family": "Goldberg", "given": "Ethan M", "initials": "EM", "orcid": "0000-0002-7404-735X", "affiliations": ["Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.", "The Epilepsy Neurogenetics Initiative, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.", "The Department of Neurology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.", "The Department of Neuroscience, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/36ba7e3b0df74614ba91bac736cbd20e.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/36ba7e3b0df74614ba91bac736cbd20e"}}, "publications": [{"entity": "publication", "iuid": "a8a78e40c92a48dca0e2226b3627c2ae", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/a8a78e40c92a48dca0e2226b3627c2ae.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/a8a78e40c92a48dca0e2226b3627c2ae"}}, "title": "A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction.", "authors": [{"family": "Clatot", "given": "Jerome", "initials": "J"}, {"family": "Currin", "given": "Christopher B", "initials": "CB"}, {"family": "Liang", "given": "Qiansheng", "initials": "Q", "orcid": "0009-0009-0856-1957", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/ee4ab9ab889143cab8c24c31605476bf.json"}}, {"family": "Pipatpolkai", "given": "Tanadet", "initials": "T"}, {"family": "Massey", "given": "Shavonne L", "initials": "SL"}, {"family": "Helbig", "given": "Ingo", "initials": "I"}, {"family": "Delemotte", "given": "Lucie", "initials": "L", "orcid": "0000-0002-0828-3899", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/87eaf619d7bd487ebdbe68c46b827e66.json"}}, {"family": "Vogels", "given": "Tim P", "initials": "TP", "orcid": "0000-0003-3295-6181", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3adfacc0cac346d082c96055f3c87fe3.json"}}, {"family": "Covarrubias", "given": "Manuel", "initials": "M"}, {"family": "Goldberg", "given": "Ethan M", "initials": "EM", "orcid": "0000-0002-7404-735X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/36ba7e3b0df74614ba91bac736cbd20e.json"}}], "type": "journal article", "published": "2024-01-16", "journal": {"title": "Proc. Natl. Acad. Sci. U.S.A.", "issn": "1091-6490", "volume": "121", "issue": "3", "pages": "e2307776121", "issn-l": "0027-8424"}, "abstract": "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 \u03c0-\u03c0 stacking interaction between the variant Tyr125 and Tyr156 in the \u03b1-6 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 \u03b3-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.", "doi": "10.1073/pnas.2307776121", "pmid": "38194456", "labels": {"Lucie Delemotte": null, "SciLifeLab Fellow": null}, "xrefs": [{"db": "pmc", "key": "PMC10801864"}], "notes": [], "created": "2024-11-26T05:26:28.255Z", "modified": "2024-11-26T05:26:28.404Z"}]}