Mutations in GABRB3: From febrile seizures to epileptic encephalopathies
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Mutations in GABRB3 : From febrile seizures to epileptic encephalopathies. / 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.
In: Neurology, Vol. 88, No. 5, 31.01.2017, p. 483-492.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Mutations in GABRB3
T2 - From febrile seizures to epileptic encephalopathies
AU - Møller, Rikke S
AU - Wuttke, Thomas V
AU - Helbig, Ingo
AU - Marini, Carla
AU - Johannesen, Katrine M
AU - Brilstra, Eva H
AU - Vaher, Ulvi
AU - Borggraefe, Ingo
AU - Talvik, Inga
AU - Talvik, Tiina
AU - Kluger, Gerhard
AU - Francois, Laurence L
AU - Lesca, Gaetan
AU - de Bellescize, Julitta
AU - Blichfeldt, Susanne
AU - Chatron, Nicolas
AU - Holert, Nils
AU - Jacobs, Julia
AU - Swinkels, Marielle
AU - Betzler, Cornelia
AU - Syrbe, Steffen
AU - Nikanorova, Marina
AU - Myers, Candace T
AU - Larsen, Line H G
AU - Vejzovic, Sabina
AU - Pendziwiat, Manuela
AU - von Spiczak, Sarah
AU - Hopkins, Sarah
AU - Dubbs, Holly
AU - Mang, Yuan
AU - Mukhin, Konstantin
AU - Holthausen, Hans
AU - van Gassen, Koen L
AU - Dahl, Hans A
AU - Tommerup, Niels
AU - Mefford, Heather C
AU - Rubboli, Guido
AU - Guerrini, Renzo
AU - Lemke, Johannes R
AU - Lerche, Holger
AU - Muhle, Hiltrud
AU - Maljevic, Snezana
N1 - © 2017 American Academy of Neurology.
PY - 2017/1/31
Y1 - 2017/1/31
N2 - 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.
AB - 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.
U2 - 10.1212/WNL.0000000000003565
DO - 10.1212/WNL.0000000000003565
M3 - Journal article
C2 - 28053010
VL - 88
SP - 483
EP - 492
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 5
ER -
ID: 172131366