Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/18396
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dc.contributor.authorLi, Melody-
dc.contributor.authorMaljevic, Snezana-
dc.contributor.authorPhillips, A Marie-
dc.contributor.authorPetrovski, Slave-
dc.contributor.authorHildebrand, Michael S-
dc.contributor.authorBurgess, Rosemary-
dc.contributor.authorMount, Therese-
dc.contributor.authorZara, Federico-
dc.contributor.authorStriano, Pasquale-
dc.contributor.authorSchubert, Julian-
dc.contributor.authorThiele, Holger-
dc.contributor.authorNürnberg, Peter-
dc.contributor.authorWong, Michael-
dc.contributor.authorWeisenberg, Judith L-
dc.contributor.authorThio, Liu Lin-
dc.contributor.authorLerche, Holger-
dc.contributor.authorScheffer, Ingrid E-
dc.contributor.authorBerkovic, Samuel F-
dc.contributor.authorPetrou, Steven-
dc.contributor.authorReid, Christopher A-
dc.date2017-11-13-
dc.date.accessioned2018-08-30T05:58:46Z-
dc.date.available2018-08-30T05:58:46Z-
dc.date.issued2018-02-
dc.identifier.citationHuman mutation 2018; 39(2): 202-209-
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/18396-
dc.description.abstractGenetic generalized epilepsy (GGE) is a common epilepsy syndrome that encompasses seizure disorders characterized by spike-and-wave discharges (SWDs). Pacemaker hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are considered integral to SWD genesis, making them an ideal gene candidate for GGE. We identified HCN2 missense variants from a large cohort of 585 GGE patients, recruited by the Epilepsy Phenome-Genome Project (EPGP), and performed functional analysis using two-electrode voltage clamp recordings from Xenopus oocytes. The p.S632W variant was identified in a patient with idiopathic photosensitive occipital epilepsy and segregated in the family. This variant was also independently identified in an unrelated patient with childhood absence seizures from a European cohort of 238 familial GGE cases. The p.V246M variant was identified in a patient with photo-sensitive GGE and his father diagnosed with juvenile myoclonic epilepsy. Functional studies revealed that both p.S632W and p.V246M had an identical functional impact including a depolarizing shift in the voltage dependence of activation that is consistent with a gain-of-function. In contrast, no biophysical changes resulted from the introduction of common population variants, p.E280K and p.A705T, and the p.R756C variant from EPGP that did not segregate with disease. Our data suggest that HCN2 variants can confer susceptibility to GGE via a gain-of-function mechanism.-
dc.language.isoeng-
dc.subjectHCN channels-
dc.subjectfebrile seizures-
dc.subjectspike-and-wave discharges-
dc.subjectthalamo-cortical networks-
dc.titleGain-of-function HCN2 variants in genetic epilepsy.-
dc.typeJournal Article-
dc.identifier.journaltitleHuman mutation-
dc.identifier.affiliationThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia-
dc.identifier.affiliationEpilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia-
dc.identifier.affiliationLaboratory of Neurogenetics, Department of Neuroscience, Institute "G. Gaslini", Genoa, Italy-
dc.identifier.affiliationPediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Institute "G. Gaslini", Genoa, Italy-
dc.identifier.affiliationCologne Centre for Genomics, University of Cologne, Cologne, Germany-
dc.identifier.affiliationDepartment of Neurology, Washington University School of Medicine and St. Louis Children's Hospital, St Louis, Missouri-
dc.identifier.affiliationSchool of Biosciences, The University of Melbourne, Parkville, Victoria, Australia-
dc.identifier.affiliationUniversity of Tübingen, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tübingen, Germany-
dc.identifier.doi10.1002/humu.23357-
dc.identifier.orcid0000-0002-2664-4395en
dc.identifier.orcid0000-0002-1527-961Xen
dc.identifier.orcid0000-0003-2739-0515en
dc.identifier.orcid0000-0003-1876-5872en
dc.identifier.orcid0000-0002-2311-2174en
dc.identifier.orcid0000-0003-4580-841Xen
dc.identifier.pubmedid29064616-
dc.type.austinJournal Article-
local.name.researcherBerkovic, Samuel F
item.languageiso639-1en-
item.cerifentitytypePublications-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.grantfulltextnone-
item.openairetypeJournal Article-
item.fulltextNo Fulltext-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptMedicine (University of Melbourne)-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptNeurology-
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