De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

被引：128

作者：

Kury, Sebastien ^{[1
]}

van Woerden, Geeske M. ^{[2
,3
]}

Besnard, Thomas ^{[1
]}

Onori, Martina Proietti ^{[2
,3
]}

Latypova, Xenia ^{[1
]}

Towne, Meghan C. ^{[4
,6
]}

Cho, Megan T. ^{[7
]}

Prescott, Trine E. ^{[8
]}

Ploeg, Melissa A. ^{[2
,3
]}

Sanders, Stephan ^{[9
]}

Stessman, Holly A. F. ^{[10
,11
]}

Pujol, Aurora ^{[12
,13
,14
]}

Ben Distel ^{[2
,3
,15
]}

Robak, Laurie A. ^{[16
]}

Bernstein, Jonathan A. ^{[17
]}

Denomme-Pichon, Anne-Sophie ^{[18
,19
]}

Lesca, Gaetan ^{[20
,21
]}

Sellars, Elizabeth A. ^{[22
]}

Berg, Jonathan ^{[23
,24
]}

Carre, Wilfrid ^{[25
]}

Busk, Oyvind Lovold ^{[8
]}

van Bon, Bregje W. M. ^{[26
]}

Waugh, Jeff L. ^{[27
]}

Deardorff, Matthew ^{[28
]}

Hoganson, George E. ^{[29
]}

Bosanko, Katherine B. ^{[22
]}

Johnson, Diana S. ^{[30
]}

Dabir, Tabib ^{[31
]}

Holla, Oystein Lunde ^{[8
]}

Sarkar, Ajoy ^{[32
]}

Tveten, Kristian ^{[8
]}

de Bellescize, Julitta ^{[33
]}

Braathen, Geir J. ^{[8
]}

Terhal, Paulien A. ^{[34
]}

Grange, Dorothy K. ^{[35
]}

van Haeringen, Arie ^{[36
]}

Lam, Christina

Mirzaa, Ghayda ^{[37
,38
,39
]}

Burton, Jennifer ^{[29
]}

Bhoj, Elizabeth J. ^{[40
,41
]}

Douglas, Jessica ^{[4
,5
]}

Santani, Avni B. ^{[42
,43
]}

Nesbitt, Addie I. ^{[42
]}

Helbig, Katherine L. ^{[44
,45
]}

Andrews, Marisa V. ^{[35
]}

Begtrup, Amber ^{[7
]}

Tang, Sha ^{[44
]}

van Gassen, Koen L. I. ^{[34
]}

Juusola, Jane ^{[7
]}

Foss, Kimberly ^{[39
]}

机构：

[1] CHU Nantes, Serv Genet Med, 9 Quai Moncousu, F-44093 Nantes 1, France

[2] Erasmus Univ, Med Ctr, Dept Neurosci, NL-3015 CN Rotterdam, Netherlands

[3] Erasmus Univ, Med Ctr, ENCORE Expertise Ctr Neurodev Disorder, NL-3015 CN Rotterdam, Netherlands

[4] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA

[5] Harvard Med Sch, Boston, MA 02115 USA

[6] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Gene Discovery Core, Boston, MA 02115 USA

[7] GeneDx, Gaithersburg, MD 20877 USA

[8] Telemark Hosp Trust, Dept Med Genet, N-3710 Skien, Norway

[9] Univ Calif San Francisco, Weill Inst Neurosci, Dept Psychiat, San Francisco, CA 94158 USA

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

[11] Creighton Univ, Sch Med, Dept Pharmacol, Omaha, NE 68178 USA

[12] IDIBELL, Neurometabol Dis Lab, Gran Via 199, Barcelona 08908, Spain

[13] Ctr Biomed Res Rare Dis, CIBERER U759, Barcelona 08908, Spain

[14] Catalan Inst Res & Adv Studies ICREA, Barcelona 08010, Spain

[15] Univ Amsterdam, Acad Med Ctr, Dept Med Biochem, NL-1105AZ Amsterdam, Netherlands

[16] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[17] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA

[18] CHU Angers, Dept Biochimie & Genet, F-49933 Angers 9, France

[19] CNRS 6015, UMR INSERM 1083, F-49933 Angers 9, France

[20] Hosp Civils Lyon, Ctr Reference Anomalies Dev, Serv Genet, F-69288 Lyon, France

[21] INSERM, Ctr Rech Neurosci Lyon, U1028, CNRS UMR5292, F-69675 Bron, France

[22] Arkansas Childrens Hosp, Sect Genet & Metab, Little Rock, AR 72202 USA

[23] Univ Dundee, Sch Med, Mol & Clin Med, Ninewells Hosp, Dundee DD1 9SY, Scotland

[24] Med Sch, Dundee DD1 9SY, Scotland

[25] CHU Rennes, Lab Genet Mol & Genom, F-35033 Rennes, France

[26] Radboud Univ Nijmegen, Dept Human Genet, Nijmegen Ctr Mol Life Sci, Inst Genet & Metab Dis,Med Ctr, NL-6525 GA Nijmegen, Netherlands

[27] Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA

[28] Childrens Hosp Philadelphia, Div Genet, Dept Pediat, Philadelphia, PA 19104 USA

[29] Univ Illinois, Dept Pediat, Coll Med, Chicago, IL 60612 USA

[30] Sheffield Childrens Hosp, Western Bank, Sheffield S10 2TH, S Yorkshire, England

[31] Belfast City Hosp, Northern Ireland Reg Genet Ctr, Belfast Hlth & Social Care Trust, Lisburn Rd, Belfast BT9 7AB, Antrim, North Ireland

[32] Univ Nottingham Hosp, NHS Trust, Nottingham Reg Genet Serv, City Hosp Campus,Hucknall Rd, Nottingham NG5 1PB, England

[33] Hosp Civils, Epilepsy Sleep & Pediat Neurophysiol Dept, F-69677 Lyon, France

[34] Univ Med Ctr Utrecht, Dept Genet, NL-3584 Utrecht, Netherlands

[35] Washington Univ, Dept Pediat, Sch Med, Div Genet & Genom Med, St Louis, MO 63110 USA

[36] LUMC, Dept Clin Genet, NL-2333 ZA Leiden, Netherlands

[37] Univ Washington, Sch Med, Dept Pediat, Div Genet Med, Seattle, WA 98105 USA

[38] Seattle Childrens Hosp, Seattle, WA 98105 USA

[39] Seattle Childrens Res Inst, Ctr Integrat Brain Res, Seattle, WA 98101 USA

[40] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[41] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA

[42] Childrens Hosp Philadelphia, Dept Path & Lab Med, Div Genom Diagnost, Philadelphia, PA 19104 USA

[43] Univ Penn, Sch Med, Dept Path & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA

[44] Div Clin Genom Ambry Genet, 15 Argonaut, Aliso Viejo, CA 92656 USA

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

[46] Heidelberg Univ, Inst Human Genet, Neuenheimer Feld 366, D-69120 Heidelberg, Germany

[47] Heidelberg Univ, Med Fac Heidelberg, D-69120 Heidelberg, Germany

[48] German Canc Res Ctr, Div Theoret Bioinformat, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[49] Univ Nantes, CNRS, INSERM, Inst Thorax, F-44007 Nantes, France

[50] CHU Nantes, Inst Thorax, F-44093 Nantes, France

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2017年 / 101卷 / 05期

关键词：

REGION-SPECIFIC REQUIREMENTS; LONG-TERM POTENTIATION; SYNAPTIC PLASTICITY; ALPHA-CAMKII; GRIN2A MUTATIONS; II ISOFORMS; IN-VIVO; EPILEPSY; IMPACT; AUTOPHOSPHORYLATION;

D O I：

10.1016/j.ajhg.2017.10.003

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

引用

页码：768 / 788

页数：21

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