Gain‐of‐function HCN2 variants in genetic epilepsy. Issue 2 (13th November 2017)

• Record Type: Journal Article
• 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.
• Is Part Of: Human mutation. Volume 39:Issue 2(2018)
• Page Start: 202
• Page End: 209
• Publication Date: 2017-11-13
• Subjects: febrile seizures -- HCN channels -- spike‐and‐wave discharges -- thalamo‐cortical networks; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23357
• Languages: English
• ISSNs: 1059-7794

Abstract

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. Abstract : Pacemaker HCN channels are integral to spike‐and‐wave discharge genesis making them ideal gene candidates for genetic generalized epilepsy (GGE). Two segregating HCN2 missense variants were identified in a cohort of 585 GGE patients. Functional analysis in Xenopus laevis oocytes revealed that HCN2 variants may confer susceptibility to GGE via a gain‐of‐function mechanism.