Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/18396
Title: Gain-of-function HCN2 variants in genetic epilepsy.
Authors: Li, Melody;Maljevic, Snezana;Phillips, A Marie;Petrovski, Slave;Hildebrand, Michael S;Burgess, Rosemary;Mount, Therese;Zara, Federico;Striano, Pasquale;Schubert, Julian;Thiele, Holger;Nürnberg, Peter;Wong, Michael;Weisenberg, Judith L;Thio, Liu Lin;Lerche, Holger;Scheffer, Ingrid E;Berkovic, Samuel F;Petrou, Steven;Reid, Christopher A
Affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Laboratory of Neurogenetics, Department of Neuroscience, Institute "G. Gaslini", Genoa, Italy
Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Institute "G. Gaslini", Genoa, Italy
Cologne Centre for Genomics, University of Cologne, Cologne, Germany
Department of Neurology, Washington University School of Medicine and St. Louis Children's Hospital, St Louis, Missouri
School of Biosciences, The University of Melbourne, Parkville, Victoria, Australia
University of Tübingen, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tübingen, Germany
Issue Date: Feb-2018
EDate: 2017-11-13
Citation: Human mutation 2018; 39(2): 202-209
Abstract: Genetic 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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/18396
DOI: 10.1002/humu.23357
ORCID: 0000-0002-2664-4395
0000-0003-1876-5872
0000-0002-2311-2174
0000-0003-4580-841X
0000-0002-1527-961X
0000-0003-2739-0515
PubMed URL: 29064616
Type: Journal Article
Subjects: HCN channels
febrile seizures
spike-and-wave discharges
thalamo-cortical networks
Appears in Collections:Journal articles

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