Cation leak: a common functional defect causing HCN1 developmental and epileptic encephalopathy.
Chaseley E McKenzie1, Ian C Forster1, Ming S Soh1
1Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia.
Brain Communications
|June 2, 2023
Summary
Pathogenic HCN1 variants cause severe developmental and epileptic encephalopathy (DEE) by increasing cation leak. This finding may help stratify patients and guide treatment for DEE caused by HCN1 mutations.
Area of Science:
- Neurogenetics
- Molecular Neuroscience
- Channelopathies
Background:
- Pathogenic variants in the HCN1 gene are a known cause of developmental and epileptic encephalopathy (DEE).
- Previous studies have not stratified HCN1-DEE patients based on the biophysical effects of specific variants on channel function.
Purpose of the Study:
- To investigate the biophysical consequences of de novo HCN1 pathogenic variants.
- To determine if cation leak is a common pathogenic mechanism in HCN1-DEE.
- To explore potential genotype-phenotype correlations for guiding clinical management.
Main Methods:
- Analysis of clinical and genetic data from eleven patients with de novo HCN1 variants.
- Functional assessment of seven HCN1 variants using two-electrode voltage-clamp recordings in Xenopus oocytes.
Main Results:
- All seven analyzed HCN1 variants resulted in a significantly increased instantaneous cation current, indicative of cation leak.
- Variability was observed in other biophysical properties, such as activation kinetics and voltage dependence.
- Published data suggest sodium channel blockers may worsen seizures in patients with HCN1 variants causing cation leak.
Conclusions:
- Cation leak is identified as a key pathogenic mechanism in HCN1-DEE.
- Stratifying patients based on the 'cation leak' phenotype could inform treatment strategies, particularly regarding sodium channel blockers.
- This research provides a foundation for personalized medicine approaches in managing HCN1-related neurological disorders.
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