Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Li, Melody UNSPECIFIED UNSPECIFIED UNSPECIFIED Maljevic, Snezana UNSPECIFIED orcid.org/0000-0003-1876-5872 UNSPECIFIED Phillips, A. Marie UNSPECIFIED UNSPECIFIED UNSPECIFIED Petrovski, Slave UNSPECIFIED UNSPECIFIED UNSPECIFIED Hildebrand, Michael S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Burgess, Rosemary UNSPECIFIED UNSPECIFIED UNSPECIFIED Mount, Therese UNSPECIFIED UNSPECIFIED UNSPECIFIED Zara, Federico UNSPECIFIED orcid.org/0000-0001-9744-5222 UNSPECIFIED Striano, Pasquale UNSPECIFIED orcid.org/0000-0002-6065-1476 UNSPECIFIED Schubert, Julian UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Wong, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Weisenberg, Judith L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thio, Liu Lin UNSPECIFIED orcid.org/0000-0002-9779-7903 UNSPECIFIED Lerche, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheffer, Ingrid E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Berkovic, Samuel F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Petrou, Steven UNSPECIFIED orcid.org/0000-0002-4960-6375 UNSPECIFIED Reid, Christopher A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language CHILDHOOD ABSENCE EPILEPSY; CHANNELS; MUTATION; SEIZURES; CACNA1H; RISK Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19828