Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy

被引：151

作者：

Lemke, Johannes R. ^{[1
]}

Geider, Kirsten ^{[3
]}

Helbig, Katherine L. ^{[4
]}

Heyne, Henrike O. ^{[1
,2
]}

Schuetz, Hannah ^{[3
]}

Hentschel, Julia ^{[1
]}

Courage, Carolina ^{[5
,6
]}

Depienne, Christel ^{[7
,8
,9
]}

Nava, Caroline ^{[7
,8
,9
]}

Heron, Delphine ^{[8
,9
]}

Moller, Rikke S. ^{[11
,12
]}

Hjalgrim, Helle ^{[11
,12
]}

Lal, Dennis ^{[13
,15
,16
,17
,18
]}

Neubauer, Bernd A. ^{[19
]}

Nuernberg, Peter ^{[13
,14
]}

Thiele, Holger ^{[13
]}

Kurlemann, Gerhard ^{[20
]}

Arnold, Georgianne L. ^{[21
]}

Bhambhani, Vikas ^{[23
]}

Bartholdi, Deborah ^{[24
]}

Pedurupillay, Christeen Ramane J. ^{[25
]}

Misceo, Doriana ^{[25
]}

Frengen, Eirik ^{[25
]}

Stromme, Petter ^{[26
]}

Dlugos, Dennis J. ^{[27
]}

Doherty, Emily S. ^{[28
]}

Bijlsma, Emilia K. ^{[29
]}

Ruivenkamp, Claudia A. ^{[29
]}

Hoffer, Mariette J. V. ^{[29
]}

Goldstein, Amy ^{[22
]}

Rajan, Deepa S. ^{[22
]}

Narayanan, Vinodh ^{[30
]}

Ramsey, Keri ^{[30
]}

Belnap, Newell ^{[30
]}

Schrauwen, Isabelle ^{[30
]}

Richholt, Ryan ^{[30
]}

Koeleman, Bobby P. C. ^{[31
]}

Sa, Joaquim ^{[32
]}

Mendonca, Carla ^{[32
]}

de Kovel, Carolien G. F. ^{[31
]}

Weckhuysen, Sarah ^{[7
,10
,33
,34
,35
]}

Hardies, Katia ^{[33
,34
]}

De Jonghe, Peter ^{[33
,34
,35
]}

De Meirleir, Linda ^{[36
]}

Milh, Mathieu ^{[37
]}

Badens, Catherine ^{[38
]}

Lebrun, Marine ^{[40
]}

Busa, Tiffany ^{[39
]}

Francannet, Christine ^{[41
]}

Piton, Amelie ^{[42
,43
]}

机构：

[1] Univ Leipzig Hosp & Clin, Inst Human Genet, Leipzig, Germany

[2] Univ Leipzig Hosp & Clin, Integrated Res & Treatment Ctr IFB Adipos Dis, Leipzig, Germany

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

[4] Ambry Genet, Div Clin Genom, Aliso Viejo, CA USA

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

[6] Folkhalsan Inst Genet, Helsinki, Finland

[7] Hop La Pitie Salpetriere, AP HP, INSERM, Paris, France

[8] Sorbonne Univ, Hop La Pitie Salpetriere, AP HP,U1127,CNRS,UMR 7225, Inst Cerveau & Moelle Epiniere ICM,Univ Paris 06, Paris, France

[9] Hop La Pitie Salpetriere, AP HP, Dept Genet, Paris, France

[10] Hop La Pitie Salpetriere, AP HP, Ctr Reference Epilepsies Rares, Epilepsy Unit, Paris, France

[11] Danish Epilepsy Ctr, Dianalund, Denmark

[12] Univ Southern Denmark, Inst Reg Hlth Serv, Odense, Denmark

[13] Univ Cologne, Cologne Ctr Genom CCG, Cologne, Germany

[14] Univ Cologne, Ctr Mol Med Cologne CMMC, Cologne, Germany

[15] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA

[16] Harvard Univ, Sch Med, Boston, MA USA

[17] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA

[18] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA

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

[20] Univ Med Ctr Munster, Dept Neuropediat, Munster, Germany

[21] Univ Pittsburgh, Sch Med, Childrens Hosp Pittsburgh, Div Med Genet,Dept Pediat, Pittsburgh, PA 15260 USA

[22] Childrens Hosp Pittsburgh, Div Child Neurol, Pittsburgh, PA 15213 USA

[23] Childrens Hosp & Clin Minnesota, Dept Med Genet, Minneapolis, MN USA

[24] Klinikum Stuttgart, Inst Clin Genet, Stuttgart, Germany

[25] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway

[26] Oslo Univ Hosp, Dept Clin Neurosci Children, Women & Childrens Div, Oslo, Norway

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

[28] Carilion Clin Childrens Hosp, Clin Genet Sect, Roanoke, VA USA

[29] Leiden Univ, Med Ctr, Dept Clin Genet, NL-2300 RA Leiden, Netherlands

[30] Translat Genom Res Inst TGen, Ctr Rare Childhood Disorders, Phoenix, AZ USA

[31] UMCU, Dept Med Genet, Utrecht, Netherlands

[32] Ctr Hosp Algarve, Faro, Portugal

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

[34] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, Antwerp, Belgium

[35] Univ Antwerp Hosp, Div Neurol, Antwerp, Belgium

[36] Vrije Univ Brussel, Univ Hosp, Dept Paediat Neurol, Brussels, Belgium

[37] Aix Marseille Univ, Hop Enfants La Timone, INSERM, GMGF UMR S 910, Marseille, France

[38] Hop Enfants La Timone, APHM, Dept Genet Med, Marseille, France

[39] Hop Enfants La Timone, Dept Genet Med, Marseille, France

[40] CHU Hop Nord, Genet Clin, Chromosom & Mol, St Pirest En Jarez, France

[41] Ctr Hosp Univ Clermont Ferrand, Serv Genet Med, Clermont Ferrand, France

[42] Univ Strasbourg, Dept Med Translat & Neurogenet, IGBMC, CNRS UMR 7104,INSERM U964, Illkirch Graffenstaden, France

[43] Hop Univ Strasbourg, Lab Diagnost Genet, Strasbourg, France

[44] CeGaT GmbH, Tubingen, Germany

[45] Swiss Epilepsy Ctr, Zurich, Switzerland

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

[47] Univ Montreal, Ctr Hosp Univ St Justine, Ctr Rech, Montreal, PQ H3C 3J7, Canada

[48] Univ Montreal, Dept Pediat, Montreal, PQ H3C 3J7, Canada

[49] Univ Montreal, Dept Neurosci, Montreal, PQ H3C 3J7, Canada

[50] Univ Heidelberg Hosp, Dept Gen Paediat, Div Child Neurol & Inherited Metab Dis, Ctr Paediat & Adolescent Med, Heidelberg, Germany

来源：

NEUROLOGY | 2016年 / 86卷 / 23期

基金：

瑞士国家科学基金会;

关键词：

INTELLECTUAL DISABILITY; MUTATIONS; EPILEPSY; DISORDERS; SUBUNITS; APHASIA; BINDING;

D O I：

10.1212/WNL.0000000000002740

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective:To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.Methods:We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.Results:We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families.Conclusions:De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.

引用

页码：2171 / 2178

页数：8

共 23 条

[1] De novo mutations in epileptic encephalopathies [J].

Allen, Andrew S. ;

Berkovic, Samuel F. ;

Cossette, Patrick ;

Delanty, Norman ;

Dlugos, Dennis ;

Eichler, Evan E. ;

Epstein, Michael P. ;

Glauser, Tracy ;

Goldstein, David B. ;

Han, Yujun ;

Heinzen, Erin L. ;

Hitomi, Yuki ;

Howell, Katherine B. ;

Johnson, Michael R. ;

Kuzniecky, Ruben ;

Lowenstein, Daniel H. ;

Lu, Yi-Fan ;

Madou, Maura R. Z. ;

Marson, Anthony G. ;

Mefford, Heather C. ;

Nieh, Sahar Esmaeeli ;

O'Brien, Terence J. ;

Ottman, Ruth ;

Petrovski, Slave ;

Poduri, Annapurna ;

Ruzzo, Elizabeth K. ;

Scheffer, Ingrid E. ;

Sherr, Elliott H. ;

Yuskaitis, Christopher J. ;

Abou-Khalil, Bassel ;

Alldredge, Brian K. ;

Bautista, Jocelyn F. ;

Berkovic, Samuel F. ;

Boro, Alex ;

Cascino, Gregory D. ;

Consalvo, Damian ;

Crumrine, Patricia ;

Devinsky, Orrin ;

Dlugos, Dennis ;

Epstein, Michael P. ;

Fiol, Miguel ;

Fountain, Nathan B. ;

French, Jacqueline ;

Friedman, Daniel ;

Geller, Eric B. ;

Glauser, Tracy ;

Glynn, Simon ;

Haut, Sheryl R. ;

Hayward, Jean ;

Helmers, Sandra L. .

NATURE, 2013, 501 (7466) :217-+

[2] GRIN2A mutations cause epilepsy-aphasia spectrum disorders [J].

Carvill, Gemma L. ;

Regan, Brigid M. ;

Yendle, Simone C. ;

O'Roak, Brian J. ;

Lozovaya, Natalia ;

Bruneau, Nadine ;

Burnashev, Nail ;

Khan, Adiba ;

Cook, Joseph ;

Geraghty, Eileen ;

Sadleir, Lynette G. ;

Turner, Samantha J. ;

Tsai, Meng-Han ;

Webster, Richard ;

Ouvrier, Robert ;

Damiano, John A. ;

Berkovic, Samuel F. ;

Shendure, Jay ;

Hildebrand, Michael S. ;

Szepetowski, Pierre ;

Scheffer, Ingrid E. ;

Mefford, Heather C. .

NATURE GENETICS, 2013, 45 (09) :1073-+

[3] Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma [J].

Dalmau, Josep ;

Tuzun, Erdem ;

Wu, Hai-yan ;

Masjuan, Jaime ;

Rossi, Jeffrey E. ;

Voloschin, Alfredo ;

Baehring, Joachim M. ;

Shimazaki, Haruo ;

Koide, Rej ;

King, Dale ;

Mason, Warren ;

Sansing, Lauren H. ;

Dichter, Marc A. ;

Rosenfeld, Myrna R. ;

Lynch, David R. .

ANNALS OF NEUROLOGY, 2007, 61 (01) :25-36

[4] Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability [J].

de Ligt, Joep ;

Willemsen, Marjolein H. ;

van Bon, Bregje W. M. ;

Kleefstra, Tjitske ;

Yntema, Helger G. ;

Kroes, Thessa ;

Vulto-van Silfhout, Anneke T. ;

Koolen, David A. ;

de Vries, Petra ;

Gilissen, Christian ;

del Rosario, Marisol ;

Hoischen, Alexander ;

Scheffer, Hans ;

de Vries, Bert B. A. ;

Brunner, Han G. ;

Veltman, Joris A. ;

Vissers, Lisenka E. L. M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 367 (20) :1921-1929

[5] Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes [J].

Endele, Sabine ;

Rosenberger, Georg ;

Geider, Kirsten ;

Popp, Bernt ;

Tamer, Ceyhun ;

Stefanova, Irina ;

Milh, Mathieu ;

Kortuem, Fanny ;

Fritsch, Angela ;

Pientka, Friederike K. ;

Hellenbroich, Yorck ;

Kalscheuer, Vera M. ;

Kohlhase, Juergen ;

Moog, Ute ;

Rappold, Gudrun ;

Rauch, Anita ;

Ropers, Hans-Hilger ;

von Spiczak, Sarah ;

Toennies, Holger ;

Villeneuve, Nathalie ;

Villard, Laurent ;

Zabel, Bernhard ;

Zenker, Martin ;

Laube, Bodo ;

Reis, Andre ;

Wieczorek, Dagmar ;

Van Maldergem, Lionel ;

Kutsche, Kerstin .

NATURE GENETICS, 2010, 42 (11) :1021-U153

[6] Anti-NMDA Receptor Encephalitis Antibody Binding Is Dependent on Amino Acid Identity of a Small Region within the GluN1 Amino Terminal Domain [J].

Gleichman, Amy J. ;

Spruce, Lynn A. ;

Dalmau, Josep ;

Seeholzer, Steven H. ;

Lynch, David R. .

JOURNAL OF NEUROSCIENCE, 2012, 32 (32) :11082-11094

[7] Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual Disability [J].

Hamdan, Fadi F. ;

Gauthier, Julie ;

Araki, Yoichi ;

Lin, Da-Ting ;

Yoshizawa, Yuhki ;

Higashi, Kyohei ;

Park, A-Reum ;

Spiegelman, Dan ;

Dobrzeniecka, Sylvia ;

Piton, Amelie ;

Tomitori, Hideyuki ;

Daoud, Hussein ;

Massicotte, Christine ;

Henrion, Edouard ;

Diallo, Ousmane ;

Shekarabi, Masoud ;

Marineau, Claude ;

Shevell, Michael ;

Maranda, Bruno ;

Mitchell, Grant ;

Nadeau, Amelie ;

D'Anjou, Guy ;

Vanasse, Michel ;

Srour, Myriam ;

Lafreniere, Ronald G. ;

Drapeau, Pierre ;

Lacaille, Jean Claude ;

Kim, Eunjoon ;

Lee, Jae-Ran ;

Igarashi, Kazuei ;

Huganir, Richard L. ;

Rouleau, Guy A. ;

Michaud, Jacques L. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2011, 88 (03) :306-316

[8] Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders [J].

Hardingham, Giles E. ;

Bading, Hilmar .

NATURE REVIEWS NEUROSCIENCE, 2010, 11 (10) :682-696

[9] Molecular determinants of agonist discrimination by NMDA receptor subunits: Analysis of the glutamate binding site on the NR2B subunit [J].

Laube, B ;

Hirai, H ;

Sturgess, M ;

Betz, H ;

Kuhse, J .

NEURON, 1997, 18 (03) :493-503

[10]

Laube B, 1998, J NEUROSCI, V18, P2954

← 1 2 3 →