Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

被引：326

作者：

Lemke, Johannes R. ^{[1
,2
]}

Lal, Dennis ^{[2
,3
,4
,5
]}

Reinthaler, Eva M. ^{[2
,6
]}

Steiner, Isabelle ^{[7
]}

Nothnagel, Michael

Alber, Michael ^{[8
]}

Geider, Kirsten ^{[9
]}

Laube, Bodo ^{[9
]}

Schwake, Michael ^{[10
]}

Finsterwalder, Katrin ^{[11
,12
]}

Franke, Andre ^{[13
]}

Schilhabel, Markus ^{[13
]}

Jaehn, Johanna A. ^{[2
,11
,12
]}

Muhle, Hiltrud ^{[2
,11
,12
]}

Boor, Rainer ^{[11
,12
,14
]}

Van Paesschen, Wim ^{[15
]}

Caraballo, Roberto ^{[16
]}

Fejerman, Natalio ^{[16
]}

Weckhuysen, Sarah ^{[2
,17
,18
,19
]}

De Jonghe, Peter ^{[2
,17
,18
,20
]}

Larsen, Jan ^{[2
,21
]}

Moller, Rikke S. ^{[2
,21
]}

Hjalgrim, Helle ^{[2
,21
]}

Addis, Laura ^{[22
]}

Tang, Shan ^{[22
]}

Hughes, Elaine ^{[23
]}

Pal, Deb K. ^{[2
,22
]}

Veri, Kadi ^{[2
,24
,25
]}

Vaher, Ulvi ^{[2
,24
,25
]}

Talvik, Tiina ^{[2
,24
,25
]}

Dimova, Petia ^{[26
]}

Lopez, Rosa Guerrero ^{[2
,27
,28
]}

Serratosa, Jose M. ^{[2
,27
,28
]}

Linnankivi, Tarja ^{[2
,29
]}

Lehesjoki, Anna-Elina ^{[2
,30
]}

Ruf, Susanne ^{[8
]}

Wolff, Markus ^{[8
]}

Buerki, Sarah ^{[31
]}

Wohlrab, Gabriele ^{[32
]}

Kroell, Judith ^{[33
]}

Datta, Alexandre N. ^{[2
,34
]}

Fiedler, Barbara ^{[35
]}

Kurlemann, Gerhard ^{[35
]}

Kluger, Gerhard ^{[36
]}

Hahn, Andreas ^{[2
,5
]}

Haberlandt, D. Edda ^{[37
]}

Kutzer, Christina ^{[38
]}

Sperner, Juergen ^{[39
]}

Becker, Felicitas ^{[2
,40
]}

Weber, Yvonne G. ^{[2
,40
]}

机构：

[1] Univ Childrens Hosp Inselspital, Div Human Genet, Bern, Switzerland

[2] Univ Cologne, Partners EuroEPINOMICS, D-50931 Cologne, Germany

[3] Univ Cologne, CCG, D-50931 Cologne, Germany

[4] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany

[5] Univ Med Ctr Giessen & Marburg, Dept Neuropediat, Giessen, Germany

[6] Med Univ Vienna, Dept Neurol, Vienna, Austria

[7] CeGaT, GmbH, Tubingen, Germany

[8] Univ Tubingen, Dept Neuropediat, Tubingen, Germany

[9] Tech Univ Darmstadt, Dept Neurophysiol & Neurosensory Syst, Darmstadt, Germany

[10] Univ Bielefeld, Dept Chem Biochem 3, D-33615 Bielefeld, Germany

[11] Univ Med Ctr Schleswig Holstein, Dept Neuropediat, Kiel, Germany

[12] Christian Albrecht Univ Kiel, Kiel, Germany

[13] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[14] No German Epilepsy Ctr Children & Adolescents, Schwentinental, Germany

[15] Univ Hosp, Dept Neurol, Louvain, Belgium

[16] Juan P Garrahan Pediat Hosp, Dept Neurol, Buenos Aires, DF, Argentina

[17] Univ Antwerp VIB, Dept Mol Genet, Neurogenet Grp, B-2610 Antwerp, Belgium

[18] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2020 Antwerp, Belgium

[19] Epilepsy Ctr Kempenhaeghe, Hans Berger Clin, Oosterhout, Netherlands

[20] Univ Antwerp Hosp, Dept Neurol, Antwerp, Belgium

[21] Danish Epilepsy Ctr, Dianalund, Denmark

[22] Kings Coll London, Kings Coll Hosp, Inst Psychiat, London, England

[23] Kings Coll London, Dept Paediat Neurosci, Neurol Clin, London, England

[24] Childrens Clin Tartu Univ Hosp, Dept Pediat, Tartu, Estonia

[25] Univ Tartu, EE-50090 Tartu, Estonia

[26] St Naum Univ Hosp Neurol & Psychiat, Clin Child Neurol, Sofia, Bulgaria

[27] Jimenez Diaz Univ Hosp, IIS Fdn, Dept Neurol, Madrid, Spain

[28] CIBERER, Madrid, Spain

[29] Univ Helsinki, Cent Hosp, Dept Pediat Neurol, Helsinki, Finland

[30] Univ Helsinki, Folkhalsan Inst Genet, Neurosci Ctr, Helsinki, Finland

[31] Univ Childrens Hosp Inselspital, Dept Neuropediat, Bern, Switzerland

[32] Univ Childrens Hosp, Neuropediat & Neurophysiol Dept, Zurich, Switzerland

[33] Swiss Epilepsy Ctr, Zurich, Switzerland

[34] Univ Childrens Hosp, Dept Neuropediat, Basel, Switzerland

[35] Univ Childrens Hosp, Univ Med Ctr Munster, Dept Neuropediat, Munster, Germany

[36] Schoen Clin Vogtareuth, Epilepsy Ctr Children & Adolescents, Dept Neuropediat & Neurorehabilitat, Vogtareuth, Germany

[37] Univ Childrens Hosp, Dept Neuropediat, Innsbruck, Austria

[38] Kinderzentrum St Martin, Regensburg, Germany

[39] Neuropediat Med Practice, Lubeck, Germany

[40] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurol & Epileptol, Tubingen, Germany

[41] Med Univ Vienna, Dept Pediat, Vienna, Austria

[42] Med Univ Vienna, St Anna Childrens Hosp, Dept Pediat, Vienna, Austria

[43] McMaster Univ, Dept Pediat, Hamilton, ON, Canada

[44] Med Univ Graz, Dept Pediat, Graz, Austria

[45] Hosp Socio Med Ctr SMZ Sud Kaiser Franz Josef Spi, Dept Pediat, Vienna, Austria

[46] UCL, Sch Pharm, Dept Pharm, London, England

[47] Univ Bonn, Inst Human Genet, Bonn, Germany

[48] Univ Basel, Div Med Genet, Basel, Switzerland

[49] Univ Hosp, Dept Biomed, Basel, Switzerland

[50] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany

来源：

NATURE GENETICS | 2013年 / 45卷 / 09期

基金：

芬兰科学院; 奥地利科学基金会;

关键词：

NMDA RECEPTOR; CENTROTEMPORAL SPIKES; SEIZURES; BENIGN; WAVES; CLASSIFICATION; TERMINOLOGY; CONTRIBUTE; COMPLEX; LINKAGE;

D O I：

10.1038/ng.2728

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS)(1,2). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 x 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.

引用

页码：1067 / +

页数：8

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