# 43 HCN1 variants in neurodevelopmental disorders sorted into four functional classes in HEK293 cells

- Published: 2026-11-05 23:40 UTC
- Section: Life & Health › Neurotechnology
- Tags: HCN1 variants, Ih current, genotype-phenotype correlation, loss-of-function variants, gain-of-function variants, selectivity filter, allosteric modulators, TRIP8b nano, patch-clamp electrophysiology
- URL: https://realtech.media/news/rt-bb19ce59c27a905c59b97abd_43_hcn1_variants/

**Patch-clamp tests in HEK293 cells, compared with data from 49 patients, linked loss-of-function variants to milder phenotypes and gain-of-function variants to epilepsy.**

![43 HCN1 variants in neurodevelopmental disorders sorted into four functional classes in HEK293 cells](https://sgzwpqqelzmajkcubgkl.supabase.co/storage/v1/object/public/rt-media/2026/11/68c3550976a40787.jpg)
*U.S. Navy photo by John F. Williams, Wikimedia Commons, Public domain*

Researchers functionally characterized 43 variants of the HCN1 gene found in patients with neurodevelopmental disorders, with or without epilepsy. They used patch-clamp electrophysiology and confocal imaging in HEK293 cells and compared the results with clinical data from a cohort of 49 patients. The work was published in Proceedings of the National Academy of Sciences [1].

HCN1 channels mediate the Ih cationic current and play a central role in regulating neuronal excitability and synaptic integration. The channel is expressed mainly in the neocortex and hippocampus. Pathogenic variants in HCN1 have been found in people with a broad spectrum of epileptic disorders, from severe developmental and epileptic encephalopathy (DEE) to milder epilepsies [1].

## Four functional classes of HCN1 variants

Based on biophysical properties, the authors defined four classes: (I) low or no current, (II) a hyperpolarizing (left) shift in voltage dependence, (III) a depolarizing (right) shift in voltage dependence, and (IV) generation of an instantaneous current [1].

## Genotype-phenotype correlation and modulators

Loss-of-function variants were strongly enriched among individuals without epilepsy or with milder generalized phenotypes. Gain-of-function and mixed variants were predominantly associated with epilepsy, including all cases of DEE [1]. Non-epileptic cases clustered within a subgroup of loss-of-function variants that affect the selectivity filter [1].

The team also tested allosteric modulators: the peptides NB6 and TRIP8b nano and the small molecule J&J12e. In these cell experiments, the modulators normalized the functional properties of mutant HCN1 channels in three of the classes [1].

The authors state that the findings provide a clinically relevant framework for interpreting HCN1 gain- and loss-of-function variants, and that the direction of channel dysfunction is a major determinant of epilepsy risk and severity [1].

## Sources

1. [Proceedings of the National Academy of Sciences](https://doi.org/10.1073/pnas.2610712123)

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Source: RealTech, realtech.media — https://realtech.media/news/rt-bb19ce59c27a905c59b97abd_43_hcn1_variants/