ArticleEpilepsia open2024
Analysis of epilepsy-associated variants in HCN3 - Functional implications and clinical observations.
Article in Epilepsia open, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Shared Disease Mechanisms in Neurodevelopmental Disorders: A Cellular and Molecular Biology Perspective.Brain sciences · 2025Review
- Hyperpolarization-activated cyclic nucleotide-gated channels and epilepsy: genetics, circuits, and treatments.Frontiers in neurology · 2025Review
- Analysis of epilepsy-associated variants in HCN3 - Functional implications and clinical observations.Epilepsia open · 2024Article
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10 authors.
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Abstract
objectiveThis case study investigates the role of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels, which are integral membrane proteins crucial for regulating neuronal excitability. HCN channels are composed of four subunits (HCN1-4), with HCN1, HCN2, and HCN4 previously linked to epilepsy. However, the role of the HCN3 in epileptogenesis remains underexplored.
methodsWe recruited a cohort of 298 epilepsy patients to screen for genetic variants in the HCN3 (NM_020897.3) using Sanger sequencing. We identified rare variants and conducted functional assays to evaluate their pathogenicity.
resultsWe identified three rare heterozygous variants in HCN3: c.1370G > A (R457H), c.1982G > A (R661Q), and c.1982G > A(P630L). In vitro functional analyses demonstrated that these variants affected the expression level of HCN3 protein without altering its membrane localization. Whole-cell voltage-clamp experiments showed that two variants (R457H and R661Q) significantly reduced current density in cells, while P630L has no effect on ion channel current. SIGNIFICANCE: Our findings suggest that the identified HCN3 genetic variants disrupt HCN ion channel function, highlighting HCN3 as a novel candidate gene involved in epileptic disorders. This expands the genetic landscape of epilepsy and provides new insights into its molecular underpinnings. PLAIN LANGUAGE SUMMARY: Epilepsy is a brain disease that can be caused by mutations in specific genes. We found three rare variants in HCN3 gene in 298 patients with epilepsy, and two of the three mutations could be pathogenic and cause epilepsy and another one is single-nucleotide polymorphism, which could have no effect and no contribution to the development of epilepsy.
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