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Study of the Functions and Activities of Neuronal K-Cl Co-Transporter KCC2 Using Western Blotting
Published on: December 9, 2022
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KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties
Maria Cristina Cioclu1,2, Ilaria Mosca3, Paolo Ambrosino4
1Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark.
Annals of Neurology
|April 16, 2023
Summary
Pathogenic KCNT2 variants cause developmental epileptic encephalopathy (DEE) with diverse neurological symptoms. In vitro studies revealed gain-of-function or loss-of-function effects, guiding potential targeted therapies.
Area of Science:
- Genetics
- Neuroscience
- Pharmacology
Background:
- Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE).
- Understanding the genotype-phenotype spectrum and functional consequences of KCNT2 variants is crucial for diagnosis and treatment.
Purpose of the Study:
- To describe the phenotypic and genetic features of patients with KCNT2-related DEE.
- To investigate the in vitro functional and pharmacological properties of KCNT2 channels with novel or previously untested variants.
Main Methods:
- Investigated 25 patients with KCNT2 variants (12 from a collaborative network, 13 from literature).
- Collected clinical data using standardized phenotyping sheets.
- Identified novel variants via exome sequencing and classified them using ACMG criteria.
- Performed whole-cell electrophysiology in HEK-293 and SH-SY5Y cells for functional and pharmacological studies.
Main Results:
- Phenotypic spectrum included intellectual disability/developmental delay, epilepsy, neurological impairment (altered muscle tone), and dysmorphisms.
- Identified 19 pathogenic KCNT2 variants (9 new, 10 reported), including missense, in-frame deletion, nonsense, and frameshift types.
- In vitro studies showed 8 variants with gain-of-function (GoF) and 6 with loss-of-function (LoF) features.
- Quinidine and fluoxetine blocked GoF variants; loxapine and riluzole showed varied effects on LoF variants.
Conclusions:
- Expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, identifying novel genotype-phenotype associations.
- Pathogenic KCNT2 variants result in GoF or LoF phenotypes in vitro, each with a unique pharmacological profile.
- In vitro functional and pharmacological investigations are essential for developing targeted therapies based on the molecular phenotype.
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