Li, Melody, Maljevic, Snezana ORCID: 0000-0003-1876-5872, Phillips, A. Marie, Petrovski, Slave, Hildebrand, Michael S., Burgess, Rosemary, Mount, Therese, Zara, Federico ORCID: 0000-0001-9744-5222, Striano, Pasquale ORCID: 0000-0002-6065-1476, Schubert, Julian, Thiele, Holger, Nuernberg, Peter, Wong, Michael, Weisenberg, Judith L., Thio, Liu Lin ORCID: 0000-0002-9779-7903, Lerche, Holger, Scheffer, Ingrid E., Berkovic, Samuel F., Petrou, Steven ORCID: 0000-0002-4960-6375 and Reid, Christopher A. (2018). Gain-of-function HCN2 variants in genetic epilepsy. Hum. Mutat., 39 (2). S. 202 - 210. HOBOKEN: WILEY. ISSN 1098-1004

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Li, MelodyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maljevic, SnezanaUNSPECIFIEDorcid.org/0000-0003-1876-5872UNSPECIFIED
Phillips, A. MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petrovski, SlaveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hildebrand, Michael S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burgess, RosemaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mount, ThereseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zara, FedericoUNSPECIFIEDorcid.org/0000-0001-9744-5222UNSPECIFIED
Striano, PasqualeUNSPECIFIEDorcid.org/0000-0002-6065-1476UNSPECIFIED
Schubert, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wong, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weisenberg, Judith L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thio, Liu LinUNSPECIFIEDorcid.org/0000-0002-9779-7903UNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffer, Ingrid E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berkovic, Samuel F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petrou, StevenUNSPECIFIEDorcid.org/0000-0002-4960-6375UNSPECIFIED
Reid, Christopher A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-198286
DOI: 10.1002/humu.23357
Journal or Publication Title: Hum. Mutat.
Volume: 39
Number: 2
Page Range: S. 202 - 210
Date: 2018
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1098-1004
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHILDHOOD ABSENCE EPILEPSY; CHANNELS; MUTATION; SEIZURES; CACNA1H; RISKMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19828

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