AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

被引：175

作者：

Salpietro, Vincenzo ^{[1
,2
,3
]}

Dixon, Christine L. ^{[4
]}

Guo, Hui ^{[5
,6
,7
]}

Bello, Oscar D. ^{[4
]}

Vandrovcova, Jana ^{[1
]}

Efthymiou, Stephanie ^{[1
,4
]}

Maroofian, Reza ^{[1
]}

Heimer, Gali ^{[8
,9
]}

Burglen, Lydie ^{[10
]}

Valence, Stephanie ^{[11
]}

Torti, Erin ^{[12
]}

Hacke, Moritz ^{[13
]}

Rankin, Julia ^{[14
]}

Tariq, Huma ^{[1
]}

Colin, Estelle ^{[15
,16
]}

Procaccio, Vincent ^{[15
,16
]}

Striano, Pasquale ^{[2
,3
]}

Mankad, Kshitij ^{[17
]}

Lieb, Andreas ^{[4
]}

Chen, Sharon ^{[18
]}

Pisani, Laura ^{[18
]}

Bettencourt, Conceicao ^{[19
,20
]}

Mannikko, Roope ^{[1
]}

Manole, Andreea ^{[1
]}

Brusco, Alfredo ^{[21
]}

Grosso, Enrico ^{[21
]}

Ferrero, Giovanni Battista ^{[22
]}

Armstrong-Moron, Judith ^{[23
]}

Gueden, Sophie ^{[24
]}

Bar-Yosef, Omer ^{[8
,9
]}

Tzadok, Michal ^{[8
,9
]}

Monaghan, Kristin G. ^{[12
]}

Santiago-Sim, Teresa ^{[12
]}

Person, Richard E. ^{[12
]}

Cho, Megan T. ^{[12
]}

Willaert, Rebecca ^{[12
]}

Yoo, Yongjin ^{[25
]}

Chae, Jong-Hee ^{[26
]}

Quan, Yingting ^{[6
,7
]}

Wu, Huidan ^{[6
,7
]}

Wang, Tianyun ^{[5
,6
,7
]}

Bernier, Raphael A. ^{[27
]}

Xia, Kun ^{[6
,7
]}

Blesson, Alyssa ^{[28
]}

Jain, Mahim ^{[28
]}

Motazacker, Mohammad M. ^{[29
]}

Jaeger, Bregje ^{[30
]}

Schneider, Amy L. ^{[31
]}

Boysen, Katja ^{[31
]}

Muir, Alison M. ^{[32
]}

机构：

[1] UCL, Inst Neurol, Dept Neuromuscular Disorders, Queen Sq, London WC1N 3BG, England

[2] IRCCS, Ist Giannina Gaslini, Pediat Neurol & Muscular Dis Unit, I-16147 Genoa, Italy

[3] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, I-16132 Genoa, Italy

[4] UCL, Inst Neurol, Dept Clin & Expt Epilepsy, Queen Sq, London WC1N 3BG, England

[5] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA

[6] Cent South Univ, Ctr Med Genet, Changsha 410083, Hunan, Peoples R China

[7] Cent South Univ, Hunan Key Lab Med Genet, Sch Life Sci, Changsha 410083, Hunan, Peoples R China

[8] Tel Aviv Univ, Safra Childrens Hosp, Sheba Med Ctr, Pediat Neurol Unit, IL-526121 Ramat Gan, Israel

[9] Tel Aviv Univ, Sackler Fac Med, IL-526121 Ramat Gan, Israel

[10] Hop Trousseau, AP HP, Ctr Reference Malformat & Malad Congenitales Cerv, Dept Genet & Embryol Med, F-75012 Paris, France

[11] Hop Trousseau, AP HP, Ctr Reference Malformat & Malad Congenitales Cerv, Serv Neurol Pediat, F-75012 Paris, France

[12] GeneDx, Gaithersburg, MD 20877 USA

[13] Heidelberg Univ, Biochem Ctr, D-69120 Heidelberg, Germany

[14] Royal Devon & Exeter NHS Fdn Trust, Exeter EX1 2ED, Devon, England

[15] Univ Hosp, Dept Biochem & Genet, F-49933 Angers, France

[16] Angers Univ, MitoVasc Inst, MitoLab, UMR CNRS 6015,INSERM U1083, F-49100 Angers, France

[17] Great Ormond St Hosp Sick Children, London WC1N 3JH, England

[18] Hofstra Univ SOM, Div Med Genet, Northwell Hlth, New York, NY 11020 USA

[19] UCL, Inst Neurol, Dept Clin & Movement Neurosci, Queen Sq, London WC1N 1PJ, England

[20] UCL, Inst Neurol, Brain Bank Neurol Disorders, Queen Sq, London WC1N 1PJ, England

[21] Univ Torino, Dept Med Sci, Med Genet Unit, I-10126 Turin, Italy

[22] Univ Torino, Dept Publ Hlth & Pediat, I-10126 Turin, Italy

[23] Univ Hosp St Joan de Deu Barcelona, Unit Med & Mol Genet, Barcelona 08950, Spain

[24] Univ Hosp, Unit Neuropediat, F-49933 Angers, France

[25] Seoul Natl Univ, Dept Biomed Sci, Seoul 03080, South Korea

[26] Seoul Natl Univ, Dept Pediat, Seoul 03080, South Korea

[27] Univ Washington, Dept Psychiat, Seattle, WA 98195 USA

[28] Kennedy Krieger Inst, Ctr Autism & Related Disorders, Baltimore, MD 21211 USA

[29] Univ Amsterdam, Dept Clin Genet, Meibergdreef 9, NL-1105 Amsterdam, Netherlands

[30] Amsterdam UMC, Dept Pediat Neurol, NL-1105 Amsterdam, Netherlands

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

[32] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

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

[34] Mayo Clin, Dept Clin Genom, Rochester, MN 55902 USA

[35] Univ Ottawa, Eastern Ontario Res Inst, Childrens Hosp, Ottawa, ON K1H 8L1, Canada

[36] McGill Univ, Dept Human Genet, Hlth Ctr, Montreal, PQ H4A 3J1, Canada

[37] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada

[38] Univ Complutense, Hosp Gen Univ Gregorio Maranon, Sch Med, Child & Adolescent Psychiat Dept,IiSGM,CIBERSAM, Madrid 28007, Spain

[39] Univ Complutense, Hosp Gen Univ Gregorio Maranon, Inst Psychiat & Mental Hlth, CIBERSAM, Madrid 28007, Spain

[40] Hosp Gregorio Maranon, Sch Med, IiSGM, Calle Dr Esquerdo 46, Madrid 28007, Spain

[41] Univ Santiago Compostela, CIBERER, CIMUS, Grp Med Xenom, Santiago De Compostela 15782, Spain

[42] Fdn Publ Galega Med Xenom IDIS, Serv Galego Saude SERGAS, Santiago De Compostela 15782, Spain

[43] Leiden Univ, Dept Clin Genet, Med Ctr, NL-2333 ZA Leiden, Netherlands

[44] Univ Hop Pitie Salpetriere, AP HP, Dept Genet, F-75013 Paris, France

[45] G DAlessandro Univ Palermo, Dept Hlth Promot Mother & Child Care, Internal Med & Med Special, I-90133 Palermo, Italy

[46] IRCCS, Ist Giannina Gaslini, Lab Neurogenet & Neurosci, I-16147 Genoa, Italy

[47] Univ Trieste, Inst Maternal & Child Hlth, IRCCS Burlo Garofolo, I-34134 Trieste, Italy

[48] Univ Autonoma Barcelona, Univ Hosp Vall dHebron, Dept Pediat Neurol, Barcelona 08035, Spain

[49] Neurosci Med Grp, 1625 Stockton Blvd,Suite 104, Sacramento, CA 95816 USA

[50] Childrens Hosp Colorado, Dept Genet & Inherited Metab Dis, Aurora, CO 80045 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

英国医学研究理事会; 美国国家卫生研究院; 中国国家自然科学基金; 英国惠康基金;

关键词：

DE-NOVO MUTATIONS; INTELLECTUAL DISABILITY; RETT-SYNDROME; DEFICIENT; PHENOTYPE; MECHANISM; EPILEPSY; GRIN2A; GLUR2; MICE;

D O I：

10.1038/s41467-019-10910-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.

引用

页数：16

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