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Two epilepsy‐associated variants in KCNA2 (KV1.2) at position H310 oppositely affect channel functional expression
Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0001-8049-3869
Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0002-6315-8732
Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0001-7952-8120
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2023 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793Article in journal (Refereed) Epub ahead of print
Abstract [en]

Two KCNA2 variants (p.H310Y and p.H310R) were discovered in paediatric patients with epilepsy and developmental delay. KCNA2 encodes KV1.2-channel subunits, which regulate neuronal excitability. Both gain and loss of KV1.2 function cause epilepsy, precluding the prediction of variant effects; and while H310 is conserved throughout the KV-channel superfamily, it is largely understudied. We investigated both variants in heterologously expressed, human KV1.2 channels by immunocytochemistry, electrophysiology and voltage-clamp fluorometry. Despite affecting the same channel, at the same position, and being associated with severe neurological disease, the two variants had diametrically opposite effects on KV1.2 functional expression. The p.H310Y variant produced ‘dual gain of function’, increasing both cell-surface trafficking and activity, delaying channel closure. We found that the latter is due to the formation of a hydrogen bond that stabilizes the active state of the voltage-sensor domain. Additionally, H310Y abolished ‘ball and chain’ inactivation of KV1.2 by KVβ1 subunits, enhancing gain of function. In contrast, p.H310R caused ‘dual loss of function’, diminishing surface levels by multiple impediments to trafficking and inhibiting voltage-dependent channel opening. We discuss the implications for KV-channel biogenesis and function, an emergent hotspot for disease-associated variants, and mechanisms of epileptogenesis. 

Place, publisher, year, edition, pages
WILEY , 2023.
Keywords [en]
channelopathy; developmental delay; fluorometry; genetics; H310Y; K+ channel; MED12L; seizure
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-198780DOI: 10.1113/jp285052ISI: 001089329700001PubMedID: 37883018OAI: oai:DiVA.org:liu-198780DiVA, id: diva2:1807680
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, 2019-00988Swedish Research Council, 2022-00574The Swedish Brain Foundation, FO2022-0003
Note

Funding: Linkoeping University Wallenberg Centre for Molecular Medicine; Knut and Alice Wallenberg Foundation; Hjaernfonden (The Swedish Brain Foundation) [FO2022-0003]; Vetenskapsradet (The Swedish Research Council) [2019-00988, 2022-00574]

Available from: 2023-10-27 Created: 2023-10-27 Last updated: 2023-11-15

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