Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/33021
Title: Cation leak: a common functional defect causing HCN1 developmental and epileptic encephalopathy.
Austin Authors: McKenzie, Chaseley E;Forster, Ian C;Soh, Ming S;Phillips, A Marie;Bleakley, Lauren E;Russ-Hall, Sophie J;Myers, Kenneth A;Scheffer, Ingrid E ;Reid, Christopher A
Affiliation: The Florey Institute of Neuroscience and Mental Health
School of Biosciences, University of Melbourne, Parkville, VIC 3052, Australia.
Epilepsy Research Centre
Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Montreal, Quebec H4A 3J1, Canada.
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, VIC 3052, Australia.
Issue Date: May-2023
Date: 2023
Publication information: Brain Communications 2023
Abstract: Pathogenic variants in HCN1 are an established cause of developmental and epileptic encephalopathy (DEE). To date, the stratification of patients with HCN1-DEE based on the biophysical consequence on channel function of a given variant has not been possible. Here, we analysed data from eleven patients carrying seven different de novo HCN1 pathogenic variants located in the transmembrane domains of the protein. All patients were diagnosed with severe disease including epilepsy and intellectual disability. The functional properties of the seven HCN1 pathogenic variants were assessed using two-electrode voltage-clamp recordings in Xenopus oocytes. All seven variants showed a significantly larger instantaneous current consistent with cation leak. The impact of each variant on other biophysical properties was variable, including changes in the half activation voltage and activation and deactivation kinetics. These data suggest that cation leak is an important pathogenic mechanism in HCN1-DEE. Furthermore, published mouse model and clinical case reports suggest that seizures are exacerbated by sodium channel blockers in patients with HCN1 variants that cause cation leak. Stratification of patients based on their 'cation leak' biophysical phenotype may therefore provide key information to guide clinical management of individuals with HCN1-DEE.
URI: https://ahro.austin.org.au/austinjspui/handle/1/33021
DOI: 10.1093/braincomms/fcad156
ORCID: 0000-0001-9022-5702
0000-0002-5689-2082
Journal: Brain Communications
Start page: fcad156
PubMed URL: 37265603
ISSN: 2632-1297
Type: Journal Article
Subjects: HCN1
cation leak
developmental and epileptic encephalopathy
electrophysiology
epilepsy
Appears in Collections:Journal articles

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