Journal article

Cation leak underlies neuronal excitability in an HCN1 developmental and epileptic encephalopathy.

Lauren E Bleakley, Chaseley E McKenzie, Ming S Soh, Ian C Forster, Paulo Pinares-Garcia, Alicia Sedo, Anirudh Kathirvel, Leonid Churilov, Nikola Jancovski, Snezana Maljevic, Samuel F Berkovic, Ingrid E Scheffer, Steven Petrou, Bina Santoro, Christopher A Reid

Brain | Oxford University Press (OUP) | Published : 2021


Pathogenic variants in HCN1 are associated with developmental and epileptic encephalopathies. The recurrent de novo HCN1 M305L pathogenic variant is associated with severe developmental impairment and drug-resistant epilepsy. We engineered the homologue Hcn1 M294L heterozygous knock-in (Hcn1M294L) mouse to explore the disease mechanism underlying an HCN1 developmental and epileptic encephalopathy. The Hcn1M294L mouse recapitulated the phenotypic features of patients with the HCN1 M305L variant, including spontaneous seizures and a learning deficit. Active epileptiform spiking on the electrocorticogram and morphological markers typical of rodent seizure models were observed in the Hcn1M294L m..

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