Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures

被引：150

作者：

Carvill, Gemma L. ^{[1
]}

McMahon, Jacinta M. ^{[2
]}

Schneider, Amy ^{[2
]}

Zemel, Matthew ^{[1
]}

Myers, Candace T. ^{[1
]}

Saykally, Julia ^{[1
]}

Nguyen, John ^{[1
]}

Robbiano, Angela ^{[3
]}

Zara, Federico ^{[3
]}

Specchio, Nicola ^{[4
]}

Mecarelli, Oriano ^{[5
]}

Smith, Robert L. ^{[6
,7
]}

Leventer, Richard J. ^{[8
,9
,10
,11
]}

Moller, Rikke S. ^{[12
,13
]}

Nikanorova, Marina ^{[12
]}

Dimova, Petia ^{[14
]}

Jordanova, Albena ^{[15
,16
,17
]}

Petrou, Steven ^{[18
]}

Helbig, Ingo ^{[19
,20
,21
]}

Striano, Pasquale ^{[22
,23
]}

Weckhuysen, Sarah ^{[15
,16
,24
]}

Berkovic, Samuel F. ^{[2
]}

Scheffer, Ingrid E. ^{[2
,8
,9
,18
]}

Mefford, Heather C. ^{[1
]}

机构：

[1] Univ Washington, Div Med Genet, Dept Pediat, Seattle, WA 98195 USA

[2] Univ Melbourne, Austin Hlth, Dept Med, Epilepsy Res Ctr, Heidelberg, Vic 3084, Australia

[3] Ist Giannina Gaslini, Dept Neurosci, Neurogenet Lab, I-16148 Genoa, Italy

[4] Bambino Gesu Childrens Hosp IRCCS, Dept Neurosci, Div Neurol, I-00165 Rome, Italy

[5] Univ Roma La Sapienza, Dept Neurol & Psychiat, I-00185 Rome, Lazio, Italy

[6] John Hunter Childrens Hosp, Dept Neurol, Newcastle, NSW 2305, Australia

[7] Univ Newcastle, Fac Hlth, Newcastle, NSW 2305, Australia

[8] Univ Melbourne, Dept Paediat, Parkville, Vic 3052, Australia

[9] Royal Childrens Hosp, Parkville, Vic 3052, Australia

[10] Royal Childrens Hosp, Dept Neurol, Parkville, Vic 3052, Australia

[11] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia

[12] Danish Epilepsy Ctr, DK-4293 Dianalund, Denmark

[13] Univ Southern Denmark, Inst Reg Hlth Serv, DK-5230 Odense, Denmark

[14] St Ivan Rilski Univ Hosp, Epilepsy Ctr, Sofia 1431, Bulgaria

[15] Univ Antwerp VIB, Dept Mol Genet, B-2610 Antwerp, Belgium

[16] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2610 Antwerp, Belgium

[17] Med Univ Sofia, Dept Med Chem & Biochem, Mol Med Ctr, Sofia 1431, Bulgaria

[18] Florey Inst Neurosci & Mental Hlth, Melbourne, Vic 3084, Australia

[19] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA

[20] Univ Med Ctr Schleswig Holstein, Dept Neuropediat, D-24118 Kiel, Germany

[21] Univ Kiel, D-24118 Kiel, Germany

[22] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, I-16148 Genoa, Italy

[23] Ist Giannina Gaslini, I-16148 Genoa, Italy

[24] Sorbonne Univ, Univ Paris 06, CNRS, INSERM,U1127,UMR 7225,UMR S 1127,Inst Cerveau & M, F-75013 Paris, France

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2015年 / 96卷 / 05期

基金：

英国医学研究理事会;

关键词：

DE-NOVO MUTATIONS; PLASMA-MEMBRANE TRANSPORTER; FEBRILE SEIZURES; GENERALIZED EPILEPSY; ASTATIC EPILEPSY; INTELLECTUAL DISABILITY; ABSENCE EPILEPSY; CEREBRAL-CORTEX; SCN1A MUTATION; PLUS;

D O I：

10.1016/j.ajhg.2015.02.016

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

GAT-1, encoded by SLC6A1, is one of the major gamma-aminobutyric acid (GABA) transporters in the brain and is responsible for re-uptake of GABA from the synapse. In this study, targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six SLC6A1 mutations in seven individuals, all of whom have epilepsy with myoclonic-atonic seizures (MAE). We describe two truncations and four missense alterations, all of which most likely lead to loss of function of GAT-1 and thus reduced GABA re-uptake from the synapse. These individuals share many of the electrophysiological properties of Gat1-deficient mice, including spontaneous spike-wave discharges. Overall, pathogenic mutations occurred in 6/160 individuals with MAE, accounting for similar to 4% of unsolved MAE cases.

引用

页码：808 / 815

页数：8

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