Cation leak: a common functional defect causing HCN1 developmental and epileptic encephalopathy.

Autor:	McKenzie CE; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia., Forster IC; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia., Soh MS; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia., Phillips AM; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia.; School of Biosciences, University of Melbourne, Parkville, VIC 3052, Australia., Bleakley LE; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia., Russ-Hall SJ; Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia., Myers KA; Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Montreal, Quebec H4A 3J1, Canada., Scheffer IE; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia.; Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, VIC 3052, Australia., Reid CA; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia.; Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
Jazyk:	angličtina
Zdroj:	Brain communications [Brain Commun] 2023 May 17; Vol. 5 (3), pp. fcad156. Date of Electronic Publication: 2023 May 17 (Print Publication: 2023).
DOI:	10.1093/braincomms/fcad156
Abstrakt:	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. Competing Interests: Ingrid Scheffer has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Rogcon, Takeda Pharmaceuticals, UCB, Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova, Nutricia, Zuellig Pharma and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin and Eisai; has served as an investigator for Anavex Life Sciences, Cerecin Inc, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder Inc, Epygenyx, ES-Therapeutics, GW Pharma, Marinus, Neurocrine BioSciences, Ovid Therapeutics, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix and Zynerba; and has consulted for Care Beyond Diagnosis, Epilepsy Consortium, Atheneum Partners, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, BioMarin, Encoded Therapeutics and Biohaven Pharmaceuticals; and is a Non-Executive Director of Bellberry Ltd and a Director of the Australian Academy of Health and Medical Sciences and the Australian Council of Learned Academies Limited. She may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc and licensed to various diagnostic companies; has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 & 2012900190 and PCT/AU2012/001321 (TECH ID:2012–009). The remaining authors report no competing interests. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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