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. 2017 Jan 31;88(5):483-492.
doi: 10.1212/WNL.0000000000003565. Epub 2017 Jan 4.

Mutations in GABRB3: From febrile seizures to epileptic encephalopathies

Rikke S Møller  1 , Thomas V Wuttke  2 , Ingo Helbig  2 , Carla Marini  2 , Katrine M Johannesen  2 , Eva H Brilstra  2 , Ulvi Vaher  2 , Ingo Borggraefe  2 , Inga Talvik  2 , Tiina Talvik  2 , Gerhard Kluger  2 , Laurence L Francois  2 , Gaetan Lesca  2 , Julitta de Bellescize  2 , Susanne Blichfeldt  2 , Nicolas Chatron  2 , Nils Holert  2 , Julia Jacobs  2 , Marielle Swinkels  2 , Cornelia Betzler  2 , Steffen Syrbe  2 , Marina Nikanorova  2 , Candace T Myers  2 , Line H G Larsen  2 , Sabina Vejzovic  2 , Manuela Pendziwiat  2 , Sarah von Spiczak  2 , Sarah Hopkins  2 , Holly Dubbs  2 , Yuan Mang  2 , Konstantin Mukhin  2 , Hans Holthausen  2 , Koen L van Gassen  2 , Hans A Dahl  2 , Niels Tommerup  2 , Heather C Mefford  2 , Guido Rubboli  2 , Renzo Guerrini  2 , Johannes R Lemke  2 , Holger Lerche  2 , Hiltrud Muhle  2 , Snezana Maljevic  2
Affiliations

Mutations in GABRB3: From febrile seizures to epileptic encephalopathies

Rikke S Møller et al. Neurology. .

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.

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Figures

Figure 1
Figure 1. GABRB3 mutations in epilepsy and pedigrees of GABRB3 multiplex families
(A) The amino acid locations of the identified GABRB3 missense mutations. (B) Pedigrees of multiplex families carrying GABRB3 mutations. DS = Dravet syndrome; EOAE = early-onset absence epilepsy; FS = febrile seizures; GEFS+ = generalized epilepsy with febrile seizures plus; GTCS = generalized tonic-clonic seizure.
Figure 2
Figure 2. Functional analysis of GABRB3 mutations using Xenopus laevis oocytes
(A) Schematic representation of the β3 subunit of the GABAA receptor, including the predicted positions of the mutated amino acids. (B) Examples of current responses to application of increasing GABA concentrations (µmol/L: 1, 3, 10, 40, 100, 300, and 1,000) recorded from Xenopus oocytes expressing wild-type (WT) α5β3γ2s receptors. (C) Normalized current response to 1 mmol/L GABA application for WT (n = 120), R429Q (n = 41), T157M (n = 39), V37G (n = 29), Y184H (n = 36), L256Q (n = 31), R111X (n = 31), and Y302C (n = 34). ****p < 0.0001, one-way analysis of variance with the Tukey multiple-comparisons test. (D) Dose-response curve for α5β3γ2s WT (n = 11), T157M (n = 6), Y302C (n = 3), and Y184H (n = 7) receptors recorded on application of different GABA concentrations (as in A) and normalized to the maximal response (1,000 µmol/L) for each cell. EC50 values were 25.3, 38.0, 326.4, and 552.3 µmol/L with the 95% confidence intervals ranging from 20.7 to 29.9, 35.4 to 40.6, 293.8 to 359.0, and 433.9 to 670.7 µmol/L for WT, T157M, Y302C, and Y184H, respectively.
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