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Functional evaluation of epilepsy-associated KCNT1 variants in multiple cellular systems reveals a predominant gain of function impact on channel properties.
Hinckley, Christopher A; Zhu, Zhonghua; Chu, Jen-Hwa; Gubbels, Cynthia; Danker, Timm; Cherry, Jonathan J; Whelan, Christopher D; Engle, Sandra J; Nguyen, Viet.
Afiliação
  • Hinckley CA; Biogen, Cambridge, Massachusetts, USA.
  • Zhu Z; Biogen, Cambridge, Massachusetts, USA.
  • Chu JH; Biogen, Cambridge, Massachusetts, USA.
  • Gubbels C; Biogen, Cambridge, Massachusetts, USA.
  • Danker T; NMI Technologietransfer GmbH, Reutlingen, Germany.
  • Cherry JJ; Biogen, Cambridge, Massachusetts, USA.
  • Whelan CD; Biogen, Cambridge, Massachusetts, USA.
  • Engle SJ; Biogen, Cambridge, Massachusetts, USA.
  • Nguyen V; Biogen, Cambridge, Massachusetts, USA.
Epilepsia ; 64(8): 2126-2136, 2023 08.
Article em En | MEDLINE | ID: mdl-37177976
ABSTRACT

OBJECTIVE:

Gain of function variants in the sodium-activated potassium channel KCNT1 have been associated with pediatric epilepsy disorders. Here, we systematically examine a spectrum of KCNT1 variants and establish their impact on channel function in multiple cellular systems.

METHODS:

KCNT1 variants identified from published reports and genetic screening of pediatric epilepsy patients were expressed in Xenopus oocytes and HEK cell lines. Variant impact on current magnitude, current-voltage relationships, and sodium ion modulation were examined.

RESULTS:

We determined basic properties of KCNT1 in Xenopus oocyte and HEK systems, including the role of extra- and intracellular sodium in regulating KCNT1 activity. The most common six KCNT1 variants demonstrated strong gain of function (GOF) effects on one or more channel properties. Analysis of 36 total variants identified phenotypic heterogeneity but a strong tendency for pathogenic variants to exert GOF effects on channel properties. By controlling intracellular sodium, we demonstrate that multiple pathogenic KCNT1 variants modulate channel voltage dependence by altering the sensitivity to sodium ions.

SIGNIFICANCE:

This study represents the largest systematic functional examination of KCNT1 variants to date. We both confirm previously reported GOF channel phenotypes and expand the number of variants with in vitro GOF effects. Our data provide further evidence that novel KCNT1 variants identified in epilepsy patients lead to disease through generalizable GOF mechanisms including increases in current magnitude and/or current-voltage relationships.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Epilepsia / Mutação com Ganho de Função Tipo de estudo: Risk_factors_studies Limite: Humans Idioma: En Revista: Epilepsia Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Epilepsia / Mutação com Ganho de Função Tipo de estudo: Risk_factors_studies Limite: Humans Idioma: En Revista: Epilepsia Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos