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

Undiagnosed Diseases Network; GEM HUGO; Deciphering Developmental Disorders Study

doi:10.1016/j.ajhg.2017.10.003

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

Undiagnosed Diseases Network
, GEM HUGO
, Deciphering Developmental Disorders Study

Department of Biological Sciences

Service de Génétique Médicale
Erasmus University Rotterdam
Boston Children's Hospital
OPKO Health, Inc.
Telemark Hospital Trust
University of California at San Francisco
University of Washington
Creighton University
Bellvitge Biomedical Research Institute
Center for Biomedical Research on Rare Diseases
ICREA
University of Amsterdam
Baylor College of Medicine
Stanford University
Université d'Angers
Institut national de la santé et de la recherche médicale
Hospices civils de Lyon
Centre de Recherche en Neurosciences de Lyon
University of Arkansas for Medical Sciences
University of Dundee
CHU de Rennes
Radboud University Nijmegen
The Children's Hospital of Philadelphia
University of Illinois Chicago
Sheffield Children's NHS Foundation Trust
Belfast Health and Social Care Trust
City Hospital
Utrecht University
Washington University St. Louis
Leiden University
Children's Hospital and Regional Medical Center Seattle
University of Pennsylvania
Ambry Genetics
Heidelberg University
German Cancer Research Center
Nantes Université
L'institut du Thorax
Baylor Genetics, LLC
Hôpital civil
Université de Strasbourg
Hôpital de Hautepierre
CHU de Brest
CHU de Poitiers
Université de Poitiers
Centre Hospitalier Régional Universitaire de Tours
Seattle Children's Hospital
Howard Hughes Medical Institute
Université Rennes1
University of Melbourne

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	768-788
Number of pages	21
Journal	American Journal of Human Genetics
Volume	101
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2017.10.003
Publication status	Published - 2 Nov 2017

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

AMPAR
CAMK2
CAMK2A
CAMK2B
NMDAR
de novo mutations
intellectual disability
synaptic plasticity

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10.1016/j.ajhg.2017.10.003

Cite this

@article{e7b31a6251604e6b9fa27d59fd1cc367,

title = "De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability",

abstract = "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.",

keywords = "AMPAR, CAMK2, CAMK2A, CAMK2B, NMDAR, de novo mutations, intellectual disability, synaptic plasticity",

author = "\{Undiagnosed Diseases Network\} and \{GEM HUGO\} and \{Deciphering Developmental Disorders Study\} and S{\'e}bastien K{\"u}ry and \{van Woerden\}, \{Geeske M.\} and Thomas Besnard and \{Proietti Onori\}, Martina and X{\'e}nia Latypova and Towne, \{Meghan C.\} and Cho, \{Megan T.\} and Prescott, \{Trine E.\} and Ploeg, \{Melissa A.\} and Stephan Sanders and Stessman, \{Holly A.F.\} and Aurora Pujol and Ben Distel and Robak, \{Laurie A.\} and Bernstein, \{Jonathan A.\} and Denomm{\'e}-Pichon, \{Anne Sophie\} and Ga{\"e}tan Lesca and Sellars, \{Elizabeth A.\} and Jonathan Berg and Wilfrid Carr{\'e} and Busk, \{{\O}yvind L{\o}vold\} and \{van Bon\}, \{Bregje W.M.\} and Waugh, \{Jeff L.\} and Matthew Deardorff and Hoganson, \{George E.\} and Bosanko, \{Katherine B.\} and Johnson, \{Diana S.\} and Tabib Dabir and Holla, \{{\O}ystein Lunde\} and Ajoy Sarkar and Kristian Tveten and \{de Bellescize\}, Julitta and Braathen, \{Geir J.\} and Terhal, \{Paulien A.\} and Grange, \{Dorothy K.\} and \{van Haeringen\}, Arie and Christina Lam and Ghayda Mirzaa and Jennifer Burton and Bhoj, \{Elizabeth J.\} and Jessica Douglas and Santani, \{Avni B.\} and Nesbitt, \{Addie I.\} and Helbig, \{Katherine L.\} and Andrews, \{Marisa V.\} and Amber Begtrup and Sha Tang and \{van Gassen\}, \{Koen L.I.\} and Jane Juusola and Grabrucker, \{Andreas M.\}",

note = "Publisher Copyright: {\textcopyright} 2017 American Society of Human Genetics",

year = "2017",

month = nov,

day = "2",

doi = "10.1016/j.ajhg.2017.10.003",

language = "English",

volume = "101",

pages = "768--788",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

number = "5",

}

TY - JOUR

T1 - De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

AU - Undiagnosed Diseases Network

AU - GEM HUGO

AU - Deciphering Developmental Disorders Study

AU - Küry, Sébastien

AU - van Woerden, Geeske M.

AU - Besnard, Thomas

AU - Proietti Onori, Martina

AU - Latypova, Xénia

AU - Towne, Meghan C.

AU - Cho, Megan T.

AU - Prescott, Trine E.

AU - Ploeg, Melissa A.

AU - Sanders, Stephan

AU - Stessman, Holly A.F.

AU - Pujol, Aurora

AU - Distel, Ben

AU - Robak, Laurie A.

AU - Bernstein, Jonathan A.

AU - Denommé-Pichon, Anne Sophie

AU - Lesca, Gaëtan

AU - Sellars, Elizabeth A.

AU - Berg, Jonathan

AU - Carré, Wilfrid

AU - Busk, Øyvind Løvold

AU - van Bon, Bregje W.M.

AU - Waugh, Jeff L.

AU - Deardorff, Matthew

AU - Hoganson, George E.

AU - Bosanko, Katherine B.

AU - Johnson, Diana S.

AU - Dabir, Tabib

AU - Holla, Øystein Lunde

AU - Sarkar, Ajoy

AU - Tveten, Kristian

AU - de Bellescize, Julitta

AU - Braathen, Geir J.

AU - Terhal, Paulien A.

AU - Grange, Dorothy K.

AU - van Haeringen, Arie

AU - Lam, Christina

AU - Mirzaa, Ghayda

AU - Burton, Jennifer

AU - Bhoj, Elizabeth J.

AU - Douglas, Jessica

AU - Santani, Avni B.

AU - Nesbitt, Addie I.

AU - Helbig, Katherine L.

AU - Andrews, Marisa V.

AU - Begtrup, Amber

AU - Tang, Sha

AU - van Gassen, Koen L.I.

AU - Juusola, Jane

AU - Grabrucker, Andreas M.

PY - 2017/11/2

Y1 - 2017/11/2

N2 - 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.

AB - 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.

KW - AMPAR

KW - CAMK2

KW - CAMK2A

KW - CAMK2B

KW - NMDAR

KW - de novo mutations

KW - intellectual disability

KW - synaptic plasticity

UR - https://www.scopus.com/pages/publications/85033605045

U2 - 10.1016/j.ajhg.2017.10.003

DO - 10.1016/j.ajhg.2017.10.003

M3 - Article

C2 - 29100089

AN - SCOPUS:85033605045

SN - 0002-9297

VL - 101

SP - 768

EP - 788

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

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

Abstract

UN SDGs

Keywords

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