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Two epilepsy‐associ...
Two epilepsy‐associated variants in KCNA2 (KV1.2) at position H310 oppositely affect channel functional expression
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- Mínguez‐Viñas, Teresa (author)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Prakash, Varsha (author)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Wang, Kaiqian (author)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Lindström, Sarah (author)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Pozzi, Serena (author)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Scott, Stuart A. (author)
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
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- Spiteri, Elizabeth (author)
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
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- Stevenson, David A. (author)
- Division of Medical Genetics, Stanford University, Palo Alto, California, USA
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- Ashley, Euan A. (author)
- Division of Medical Genetics, Stanford University, Palo Alto, California, USA
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- Gunnarsson, Cecilia, 1970- (author)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten,Region Östergötland, Klinisk genetik,Region Östergötland, Övr Regionledningskontoret
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- Pantazis, Antonios (author)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten,Wallenberg Center for Molecular Medicine
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(creator_code:org_t)
- WILEY, 2023
- 2023
- English.
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In: Journal of Physiology. - : WILEY. - 0022-3751 .- 1469-7793. ; 601:23, s. 5367-5389
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- channelopathy; developmental delay; fluorometry; genetics; H310Y; K+ channel; MED12L; seizure
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Mínguez‐Viñas, T ...
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Prakash, Varsha
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Wang, Kaiqian
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Lindström, Sarah
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Pozzi, Serena
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Scott, Stuart A.
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Spiteri, Elizabe ...
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Stevenson, David ...
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Ashley, Euan A.
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Gunnarsson, Ceci ...
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Pantazis, Antoni ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Journal of Physi ...
- By the university
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Linköping University