Mutations in GABRB3
| Autor: | Sarah von Spiczak, Sabina Vejzovic, Nicolas Chatron, Laurence L Francois, Guido Rubboli, Julitta de Bellescize, Konstantin Mukhin, Holger Lerche, Marielle E M Swinkels, Johannes R. Lemke, Julia Jacobs, Susanne Blichfeldt, Hans Holthausen, Gaetan Lesca, Inga Talvik, Niels Tommerup, Heather C Mefford, Hiltrud Muhle, Tiina Talvik, Cornelia Betzler, Holly Dubbs, Line H.G. Larsen, Gerhard Kluger, Candace T. Myers, Renzo Guerrini, Steffen Syrbe, Yuan Mang, Marina Nikanorova, Sarah Hopkins, Ingo Helbig, Katrine M Johannesen, Snezana Maljevic, Ingo Borggraefe, Thomas V. Wuttke, Manuela Pendziwiat, Nils Holert, Hans Atli Dahl, Koen L.I. van Gassen, Rikke S. Møller, Carla Marini, Ulvi Vaher, Eva H. Brilstra |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Proband Heterozygote Patch-Clamp Techniques Biology Bioinformatics medicine.disease_cause Article Membrane Potentials Cohort Studies Xenopus laevis 03 medical and health sciences Epilepsy 0302 clinical medicine Journal Article medicine Animals Humans Child Automation Laboratory Genetics Mutation Massive parallel sequencing Infant Newborn High-Throughput Nucleotide Sequencing Infant Heterozygote advantage West Syndrome Receptors GABA-A medicine.disease Phenotype 030104 developmental biology Child Preschool Oocytes GABAergic Female Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | Møller, R S, Wuttke, T V, Helbig, I, Marini, C, Johannesen, K M, Brilstra, E H, Vaher, U, Borggraefe, I, Talvik, I, Talvik, T, Kluger, G, Francois, L L, Lesca, G, de Bellescize, J, Blichfeldt, S, Chatron, N, Holert, N, Jacobs, J, Swinkels, M E M, Betzler, C, Syrbe, S, Nikanorova, M, Myers, C T, Larsen, L H G, Vejzovic, S, Pendziwiat, M, von Spiczak, S, Hopkins, S, Dubbs, H, Mang, Y, Mukhin, K, Holthausen, H, van Gassen, K L, Dahl, H A, Tommerup, N, Mefford, H C, Rubboli, G, Guerrini, R, Lemke, J R, Lerche, H, Muhle, H & Maljevic, S 2017, ' Mutations in GABRB3 : From febrile seizures to epileptic encephalopathies ', Neurology, vol. 88, no. 5, pp. 483-492 . https://doi.org/10.1212/WNL.0000000000003565 |
| ISSN: | 1526-632X 0028-3878 |
| DOI: | 10.1212/wnl.0000000000003565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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