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Brain Commun
2023 Jan 01;53:fcad156. doi: 10.1093/braincomms/fcad156.
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Cation leak: a common functional defect causing HCN1 developmental and epileptic encephalopathy.
McKenzie CE
,
Forster IC
,
Soh MS
,
Phillips AM
,
Bleakley LE
,
Russ-Hall SJ
,
Myers KA
,
Scheffer IE
,
Reid CA
.
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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.
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,
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Lauxmann,
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Lee,
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Lucariello,
Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype.
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Marini,
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Merseburg,
Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy.
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Nava,
De novo mutations in HCN1 cause early infantile epileptic encephalopathy.
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Palmer,
Natural History Studies and Clinical Trial Readiness for Genetic Developmental and Epileptic Encephalopathies.
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Porro,
Do the functional properties of HCN1 mutants correlate with the clinical features in epileptic patients?
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Ramentol,
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2020,
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Scheffer,
ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology.
2017,
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Scheffer,
Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice.
2023,
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Specchio,
International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions.
2022,
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Symonds,
Epilepsy and developmental disorders: Next generation sequencing in the clinic.
2020,
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Wahl-Schott,
HCN channels: structure, cellular regulation and physiological function.
2009,
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Wang,
Gene mutational analysis in a cohort of Chinese children with unexplained epilepsy: Identification of a new KCND3 phenotype and novel genes causing Dravet syndrome.
2019,
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Wolff,
Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.
2017,
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Wu,
A second S4 movement opens hyperpolarization-activated HCN channels.
2021,
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Xie,
Novel HCN1 Mutations Associated With Epilepsy and Impacts on Neuronal Excitability.
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