Mutations in GABRB3: From febrile seizures to epileptic encephalopathies

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

doi:10.1212/WNL.0000000000003565

Mutations in GABRB3: From febrile seizures to epileptic encephalopathies

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

^*Corresponding author af dette arbejde

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Publikation: Bidrag til tidsskrift › Artikel › Forskning › peer review

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.

Originalsprog	Engelsk
Sider (fra-til)	483-492
Antal sider	10
Tidsskrift	Neurology
Vol/bind	88
Udgave nummer	5
DOI	https://doi.org/10.1212/WNL.0000000000003565
Status	Udgivet - 31 jan. 2017

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10.1212/WNL.0000000000003565

Citationsformater

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., ... Maljevic, S. (2017). Mutations in GABRB3: From febrile seizures to epileptic encephalopathies. Neurology, 88(5), 483-492. https://doi.org/10.1212/WNL.0000000000003565

@article{076156b0cff24a28a6f4440d5de51640,

title = "Mutations in GABRB3: From febrile seizures to epileptic encephalopathies",

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.",

keywords = "Animals, Automation, Laboratory, Child, Child, Preschool, Cohort Studies, Epilepsy/genetics, Female, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Male, Membrane Potentials/physiology, Mutation, Oocytes, Patch-Clamp Techniques, Phenotype, Receptors, GABA-A/genetics, Xenopus laevis",

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

note = "{\textcopyright} 2017 American Academy of Neurology.",

year = "2017",

month = jan,

day = "31",

doi = "10.1212/WNL.0000000000003565",

language = "English",

volume = "88",

pages = "483--492",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "5",

}

Møller, RS, Wuttke, TV, Helbig, I, Marini, C, Johannesen, KM, Brilstra, EH, Vaher, U, Borggraefe, I, Talvik, I, Talvik, T, Kluger, G, Francois, LL, Lesca, G, de Bellescize, J, Blichfeldt, S, Chatron, N, Holert, N, Jacobs, J, Swinkels, M, Betzler, C, Syrbe, S, Nikanorova, M, Myers, CT, Larsen, LHG, Vejzovic, S, Pendziwiat, M, von Spiczak, S, Hopkins, S, Dubbs, H, Mang, Y, Mukhin, K, Holthausen, H, van Gassen, KL, Dahl, HA, Tommerup, N, Mefford, HC, Rubboli, G, Guerrini, R, Lemke, JR, Lerche, H, Muhle, H & Maljevic, S 2017, 'Mutations in GABRB3: From febrile seizures to epileptic encephalopathies', Neurology, bind 88, nr. 5, s. 483-492. https://doi.org/10.1212/WNL.0000000000003565

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

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.

KW - Animals

KW - Automation, Laboratory

KW - Child

KW - Child, Preschool

KW - Cohort Studies

KW - Epilepsy/genetics

KW - Female

KW - Heterozygote

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Male

KW - Membrane Potentials/physiology

KW - Mutation

KW - Oocytes

KW - Patch-Clamp Techniques

KW - Phenotype

KW - Receptors, GABA-A/genetics

KW - Xenopus laevis

U2 - 10.1212/WNL.0000000000003565

DO - 10.1212/WNL.0000000000003565

M3 - Article

C2 - 28053010

SN - 0028-3878

VL - 88

SP - 483

EP - 492

JO - Neurology

JF - Neurology

IS - 5

ER -

Mutations in GABRB3: From febrile seizures to epileptic encephalopathies

Abstract

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