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

Sébastien Küry; Geeske M. van Woerden; Thomas Besnard; Martina Proietti Onori; Xénia Latypova; Meghan C. Towne; Megan T. Cho; Trine E. Prescott; Melissa A. Ploeg; Stephan Sanders; Holly A.F. Stessman; Aurora Pujol; Ben Distel; Laurie A. Robak; Jonathan A. Bernstein; Anne Sophie Denommé-Pichon; Gaëtan Lesca; Elizabeth A. Sellars; Jonathan Berg; Wilfrid Carré; Øyvind Løvold Busk; Bregje W.M. van Bon; Jeff L. Waugh; Matthew Deardorff; George E. Hoganson; Katherine B. Bosanko; Diana S. Johnson; Tabib Dabir; Øystein Lunde Holla; Ajoy Sarkar; Kristian Tveten; Julitta de Bellescize; Geir J. Braathen; Paulien A. Terhal; Dorothy K. Grange; Arie van Haeringen; Christina Lam; Ghayda Mirzaa; Jennifer Burton; Elizabeth J. Bhoj; Jessica Douglas; Avni B. Santani; Addie I. Nesbitt; Katherine L. Helbig; Marisa V. Andrews; Amber Begtrup; Sha Tang; Koen L.I. van Gassen; Jane Juusola; Kimberly Foss

doi:10.1016/j.ajhg.2017.10.003

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

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

Sébastien Küry, Geeske M. van Woerden, Thomas Besnard, Martina Proietti Onori, Xénia Latypova, Meghan C. Towne, Megan T. Cho, Trine E. Prescott, Melissa A. Ploeg, Stephan Sanders, …

American journal of human genetics, Vol.101(5), pp.768-788

101

11/02/2017

DOI: https://doi.org/10.1016/j.ajhg.2017.10.003

PMID: 29100089

Abstract

Genetics

Genetics(clinical)

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.

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Title: De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability
Creators: Sébastien Küry (Author) - Centre Hospitalier Universitaire
Geeske M. van Woerden (Author) - Erasmus University Rotterdam
Thomas Besnard (Author) - Centre Hospitalier Universitaire
Martina Proietti Onori (Author) - Erasmus University Rotterdam
Xénia Latypova (Author) - Centre Hospitalier Universitaire
Meghan C. Towne (Author) - Harvard University
Megan T. Cho (Author) - GeneDX Inc
Trine E. Prescott (Author) - Sykehuset Telemark
Melissa A. Ploeg (Author) - Erasmus University Rotterdam
Stephan Sanders (Author) - University of California at San Francisco
Holly A.F. Stessman (Author) - Department of Pharmacology and Neuroscience
Aurora Pujol (Author) - Bellvitge Biomedical Research Institute;Instituto de Salud Carlos III;ICREA
Ben Distel (Author) - Erasmus University Rotterdam;University of Amsterdam
Laurie A. Robak (Author) - Baylor College of Medicine
Jonathan A. Bernstein (Author) - Stanford University
Anne Sophie Denommé-Pichon (Author) - Université d'Angers;Institut national de la santé et de la recherche médicale
Gaëtan Lesca (Author) - Hospices Civils de Lyon-Centre Léon Bérard;Centre de Recherche en Neurosciences de Lyon
Elizabeth A. Sellars (Author) - University of Arkansas for Medical Sciences
Jonathan Berg (Author) - University of Dundee
Wilfrid Carré (Author) - CHU de Rennes
Øyvind Løvold Busk (Author) - Sykehuset Telemark
Bregje W.M. van Bon (Author) - Radboud University Nijmegen
Jeff L. Waugh (Author) - Harvard University
Matthew Deardorff (Author) - University of Pennsylvania
George E. Hoganson (Author) - University of Illinois at Chicago
Katherine B. Bosanko (Author) - University of Arkansas for Medical Sciences
Diana S. Johnson (Author) - Sheffield Children's NHS Foundation Trust
Tabib Dabir (Author) - Belfast Health and Social Care Trust
Øystein Lunde Holla (Author) - Sykehuset Telemark
Ajoy Sarkar (Author) - Nottingham University Hospitals NHS Trust
Kristian Tveten (Author) - Sykehuset Telemark
Julitta de Bellescize (Author) - Hospices Civils de Lyon-Centre Léon Bérard
Geir J. Braathen (Author) - Sykehuset Telemark
Paulien A. Terhal (Author) - Utrecht University
Dorothy K. Grange (Author) - Washington University St. Louis
Arie van Haeringen (Author) - Leiden University
Christina Lam (Author) - University of Washington
Ghayda Mirzaa (Author) - University of Washington;Children's Hospital and Regional Medical Center Seattle
Jennifer Burton (Author) - University of Illinois at Chicago
Elizabeth J. Bhoj (Author) - University of Pennsylvania
Jessica Douglas (Author) - Harvard University
Avni B. Santani (Author) - University of Pennsylvania
Addie I. Nesbitt (Author) - University of Pennsylvania
Katherine L. Helbig (Author) - Ambry Genetics;University of Pennsylvania
Marisa V. Andrews (Author) - Washington University St. Louis
Amber Begtrup (Author) - GeneDX Inc
Sha Tang (Author) - Ambry Genetics
Koen L.I. van Gassen (Author) - Utrecht University
Jane Juusola (Author) - GeneDX Inc
Kimberly Foss (Author) - Children's Hospital and Regional Medical Center Seattle
Publication Details: American journal of human genetics, Vol.101(5), pp.768-788
Series: 101
Number of pages: 21
Identifiers: 991005930210602656
Academic Unit: Pharmacology and Neuroscience
Language: English
Resource Type: Journal article