Author:
Møller Rikke S.,Wuttke Thomas V.,Helbig Ingo,Marini Carla,Johannesen Katrine M.,Brilstra Eva H.,Vaher Ulvi,Borggraefe Ingo,Talvik Inga,Talvik Tiina,Kluger Gerhard,Francois Laurence L.,Lesca Gaetan,de Bellescize Julitta,Blichfeldt Susanne,Chatron Nicolas,Holert Nils,Jacobs Julia,Swinkels Marielle,Betzler Cornelia,Syrbe Steffen,Nikanorova Marina,Myers Candace T.,Larsen Line H.G.,Vejzovic Sabina,Pendziwiat Manuela,von Spiczak Sarah,Hopkins Sarah,Dubbs Holly,Mang Yuan,Mukhin Konstantin,Holthausen Hans,van Gassen Koen L.,Dahl Hans A.,Tommerup Niels,Mefford Heather C.,Rubboli Guido,Guerrini Renzo,Lemke Johannes R.,Lerche Holger,Muhle Hiltrud,Maljevic Snezana
Abstract
Objective:To examine the role of mutations in GABRB3 encoding the β3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes.Methods:We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs.Results:We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant β3, together with α5 and γ2s subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations.Conclusions:Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism.
Publisher
Ovid Technologies (Wolters Kluwer Health)
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