A Novel GABRG2 mutation, p.R136*, in a family with GEFS plus and extended phenotypes

NEUROBIOLOGY OF DISEASE

卷:64

Article

Johnston, Ann J.^1,2,3  Kang, Jing-Qiong⁴  Shen, Wangzhen⁴  Pickrell, William O.^1,2,3  Cushion, Thomas D.²  Davies, Jeffrey S.²  Baer, Kristin²  Mullins, Jonathan G. L.⁵  Hammond, Carrie L.^1,2  Chung, Seo-Kyung^1,2  Thomas, Rhys H.^1,2,3  White, Cathy^1,6  Smith, Phil E. M.³  Macdonald, Robert L.⁴  Rees, Mark I.^1,2 

[1] Swansea Univ, Coll Med, Inst Life Sci, Wales Epilepsy Res Network, Swansea SA2 8PP, W Glam, Wales

[2] Swansea Univ, Coll Med, Inst Life Sci, Neurol & Mol Neurosci Res Grp, Singleton 8PP, Wales

[3] Univ Wales Hosp, Dept Neurol, Cardiff CF14 4X, S Glam, Wales

[4] Vanderbilt Univ, Med Ctr, Dept Neurol, Nashville, TN 37232 USA

[5] Swansea Univ, Coll Med, Inst Life Sci, Swansea SA2 8PP, W Glam, Wales

[6] Abertawe Bromorgannwg Univ Hlth Board, Singleton Hosp, Swansea SA2 8PP, W Glam, Wales

关键词: GABAA receptors;    Epilepsy;    Protein truncating mutations;    Receptor trafficking;   

DOI  :  10.1016/j.nbd.2013.12.013

来源: Elsevier

【 摘 要 】

Genetic mutations in voltage-gated and ligand-gated ion channel genes have been identified in a small number of Mendelian families with genetic generalised epilepsies (GGEs). They are commonly associated with febrile seizures (FS), childhood absence epilepsy (CAE) and particularly with generalised or genetic epilepsy with febrile seizures plus (GEFS +). In clinical practice, despite efforts to categorise epilepsy and epilepsy families into syndromic diagnoses, many generalised epilepsies remain unclassified with a presumed genetic basis. During the systematic collection of epilepsy families, we assembled a cohort of families with evidence of GEFS + and screened for variations in the gamma 2 subunit of the gamma-aminobutyric acid (GABA) type A receptor gene (GABRG2). We detected a novel GABRG2(p.R136*) premature translation termination codon in one index-case from a two-generation nuclear family, presenting with an unclassified GGE, a borderline GEFS+ phenotype with learning difficulties and extended behavioural presentation. The GABRG2(p.R136*) mutation segregates with the febrile seizure component of this family's GGE and is absent in 190 healthy control samples. In vitro expression assays demonstrated that gamma 2(p.R136*) subunits were produced, but had reduced cell-surface and total expression. When gamma 2(p.R136*) subunits were co-expressed with alpha l and 132 subunits in HEK 293T cells, GABA-evoked currents were reduced. Furthermore, gamma 2(p.R136*) subunits were highly-expressed in intracellular aggregations surrounding the nucleus and endoplasmic reticulum (ER), suggesting compromised receptor trafficking. A novel GABRG2(p.R136*) mutation extends the spectrum of GABRG2 mutations identified in GEFS + and GGE phenotypes, causes GABAA receptor dysfunction, and represents a putative epilepsy mechanism. (c) 2014 Elsevier Inc All rights reserved.

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