Functional consequences of a KCNT1 variant associated with status dystonicus and early-onset infantile encephalopathy.
Ann Clin Transl Neurol
; 6(9): 1606-1615, 2019 09.
Article
em En
| MEDLINE
| ID: mdl-31560846
ABSTRACT
OBJECTIVE:
We identified a novel de novo KCNT1 variant in a patient with early-infantile epileptic encephalopathy (EIEE) and status dystonicus, a life-threatening movement disorder. We determined the functional consequences of this variant on the encoded KNa 1.1 channel to investigate the molecular mechanisms responsible for this disorder.METHODS:
A retrospective case review of the proband is presented. We performed manual and automated electrophysiologic analyses of the KCNT1-L437F variant expressed heterologously in Chinese hamster ovary (CHO) cells in the presence of channel activators/blockers.RESULTS:
The KCNT1-L437F variant, identified in a patient with refractory EIEE and status dystonicus, confers a gain-of-function channel phenotype characterized by instantaneous, voltage-dependent activation. Channel openers do not further increase L437F channel function, suggesting maximal activation, whereas channel blockers similarly block wild-type and variant channels. We further demonstrated that KCNT1 current can be measured on a high-throughput automated electrophysiology platform with potential value for future screening of novel and repurposed pharmacotherapies.INTERPRETATION:
A novel pathogenic variant in KCNT1 associated with early-onset, medication-refractory epilepsy and dystonia causes gain-of-function with rapid activation kinetics. Our findings extend the genotype-phenotype relationships of KCNT1 variants to include severe dystonia.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Espasmos Infantis
/
Distonia
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Canais de Potássio Ativados por Sódio
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Proteínas do Tecido Nervoso
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Child
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Child, preschool
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Humans
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Infant
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Male
Idioma:
En
Revista:
Ann Clin Transl Neurol
Ano de publicação:
2019
Tipo de documento:
Article