GABRB3基因的突变：从热性惊厥到癫痫性脑病
Mutations in GABRB3: From febrile seizures to epileptic encephalopathies.
作者信息
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
机构信息
From the Danish Epilepsy Centre (R.S.M., K.M.J., M.N.), Dianalund; Institute for Regional Health Services (R.S.M., K.M.J., M.N.), University of Southern Denmark, Odense; Department of Neurology and Epileptology (T.V.W., S.V., H.L., S.M.), Hertie Institute for Clinical Brain Research, and Department of Neurosurgery (T.V.W.), University of Tübingen; Department of Neuropediatrics (I.H., M.P., S.v.S., H.M.), University Medical Center Schleswig-Holstein, Kiel, Germany; Division of Neurology (I.H., S.H., H.D.), The Children's Hospital of Philadelphia, PA; Neuroscience Department (C.M., R.G.), Children's Hospital Anna Meyer-University of Florence, Italy; Department of Genetics (E.H.B., M.S., K.L.v.G.), University Medical Center Utrecht, the Netherlands; Department of Neurology and Neurorehabilitation (U.V., I.T., T.T.), Children's Clinic of Tartu University Hospital, Estonia; Department of Pediatric Neurology and Epilepsy Center (I.B.), LMU Munich, Germany; Department of Pediatrics (I.T., T.T.), University of Tartu; Tallinn Children's Hospital (I.T.), Tallinn, Estonia; Clinic for Neuropediatrics and Neurorehabilitation (G.K., C.B., H.H.), Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Germany; Paracelsus Medical Private University (G.K.), Salzburg, Austria; Neuropeadiatric Department (L.L.F.), Hospices Civils de Lyon; Department of Genetics (G.L., N.C.), Lyon University Hospitals; Claude Bernard Lyon I University (G.L., N.C.); Lyon Neuroscience Research Centre (G.L., N.C.), CNRS UMR5292, INSERM U1028; Epilepsy, Sleep and Pediatric Neurophysiology Department (J.d.B.), Lyon University Hospitals, France; Clinic for Pediatric Neurology (S.B.), Pediatric Department, University Hospital, Herlev, Denmark; Kleinwachau (N.H.), Sächsisches Epilepsiezentrum Radeberg, Dresden; Department of Neuropediatrics/Epilepsy Center (J.J.), University Medical Center Freiburg; Department of General Paediatrics (S.S.), Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg; Department of Women and Child Health (S.S.), Hospital for Children and Adolescents, University of Leipzig Hospitals and Clinics, Germany; Department of Pediatrics (C.T.M., H.C.M.), Division of Genetic Medicine, University of Washington, Seattle; Amplexa Genetics (L.H.G.L., H.A.D.), Odense, Denmark; Northern German Epilepsy Center for Children and Adolescents (S.v.S.), Schwentinental-Raisdorf, Germany; Wilhelm Johannsen Centre for Functional Genome Research (Y.M., N.T.), Department of Cellular and Molecular Medicine, University of Copenhagen; Danish Epilepsy Center (G.R.), Filadelfia/University of Copenhagen, Denmark; Department of Diagnostics (J.R.L.), Institute of Human Genetics, University of Leipzig; and Svt. Luka's Institute of Child Neurology and Epilepsy (K.M.), Moscow, Russia. Dr Maljevic is currently at the Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.
出版信息
Neurology. 2017 Jan 31;88(5):483-492. doi: 10.1212/WNL.0000000000003565. Epub 2017 Jan 4.
OBJECTIVE
To examine the role of mutations in GABRB3 encoding the β subunit of the GABA 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 β, together with α and γ 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.
目的
探讨编码γ-氨基丁酸（GABA）受体β亚基的GABRB3基因突变在个别癫痫患者中的因果关系、遗传变异谱、病理生理学及相关表型。
方法
我们对416例患有一系列癫痫性脑病和儿童期起病癫痫的患者进行了GABRB3的大规模平行测序，并从其他研究和诊断项目中招募了更多携带GABRB3突变的癫痫患者。
结果
我们鉴定出22例GABRB3杂合突变患者，其中包括来自多个家庭的3名先证者。突变携带者的表型谱范围从单纯热性惊厥、伴有热性惊厥附加症的遗传性癫痫、肌阵挛-失张力发作癫痫到韦斯特综合征及其他类型的严重早发性癫痫性脑病。利用野生型或突变型β亚基与α和γ亚基共表达，并结合自动双微电极电压钳系统，对非洲爪蟾卵母细胞中的7种突变进行电生理分析，结果显示7种突变中有5种突变导致GABA诱导的电流幅度降低或GABA敏感性降低。
结论
我们的结果表明，GABRB3突变与广泛的癫痫表型谱相关，受体功能降低导致GABA能抑制解除是相关的疾病机制。
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