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

Sébastien Küry 1, * Geeske Van Woerden 2, 3 Thomas Besnard 1 Martina Onori 2, 3 Xénia Latypova 1 Meghan Towne 4, 5 Megan Cho 6 Trine Prescott 7 Melissa Ploeg 2, 3 Stephan Sanders 8 Holly Stessman 9, 10 Aurora Pujol 11, 12, 13 Ben Distel 2, 3, 14 Laurie Robak 15 Jonathan Bernstein 16 Anne-Sophie Denommé-Pichon 17, 18 Gaëtan Lesca 19, 20 Elizabeth Sellars 21 Jonathan Berg 22 Wilfrid Carré 23 Øyvind Busk 7 Bregje Van Bon 24 Jeff Waugh 25 Matthew Deardorff 26 George Hoganson 27 Katherine Bosanko 21 Diana Johnson 28 Tabib Dabir 29 Øystein Lunde Holla 7 Ajoy Sarkar 30 Kristian Tveten 7 Julitta De Bellescize 31 Geir Braathen 7 Paulien Terhal 32 Dorothy Grange 33 Arie Van Haeringen 34 Christina Lam 35 Ghayda Mirzaa 35, 36 Jennifer Burton 27 Elizabeth Bhoj 37, 38 Jessica Douglas 4 Avni Santani 39, 40 Addie Nesbitt 39 Katherine Helbig 41, 42 Marisa Andrews 33 Amber Begtrup 6 Sha Tang 41 Koen L.I. Van Gassen 32 Jane Juusola 6 Kimberly Foss 36 Gregory Enns 16 Ute Moog 43 Katrin Hinderhofer 43 Nagarajan Paramasivam 44 Sharyn Lincoln 4 Brandon Kusako 4 Pierre Lindenbaum 45 Eric Charpentier 45 Catherine Nowak 4 Elouan Cherot 23 Thomas Simonet 31 Claudia A.L. Ruivenkamp 34 Sihoun Hahn 35 Catherine Brownstein 4, 5 Fan Xia 15, 46 Sébastien Schmitt 1 Wallid Deb 1 Dominique Bonneau 17, 18 Mathilde Nizon 1 Delphine Quinquis 1 Jamel Chelly 47, 48, 49 Gabrielle Rudolf 48, 49, 50 Damien Sanlaville 19, 20 Philippe Parent 51 Brigitte Gilbert-Dussardier 52 Annick Toutain 53 Vernon Sutton 46 Jenny Thies 35 Lisenka E.L.M. Peart-Vissers 24 Pierre Boisseau 1 Marie Vincent 1 Andreas Grabrucker 54, 55 Christèle Dubourg 23 Undiagnosed Diseases Network 4 Wen-Hann Tan 4 Nienke Verbeek 32 Martin Granzow 43 Gijs W.E. Santen 34 Jay Shendure 9, 56 Bertrand Isidor 1 Laurent Pasquier 57 Richard Redon 45 Yaping Yang 15, 46 Matthew State 58 Tjitske Kleefstra 24 Benjamin Cogné 1 Gem Hugo 59 Deciphering Study 60 Slavé Petrovski 61 Kyle Retterer 6 Evan Eichler 9, 56 Jill Rosenfeld 15 Pankaj Agrawal 4, 5, 62 Stéphane Bézieau 63, 1 Sylvie Odent 57 Ype Elgersma 2, 3, * Sandra Mercier 1
* Auteur correspondant
63 CRCINA - Département INCIT - Equipe 1 - Immunobiology of Human αβ and γδ T cells and Immunotherapeutic Applications
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
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.
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American Journal of Human Genetics, Elsevier (Cell Press), 2017, 101 (5), pp.768 - 788. 〈10.1016/j.ajhg.2017.10.003〉
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Sébastien Küry, Geeske Van Woerden, Thomas Besnard, Martina Onori, Xénia Latypova, et al.. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. American Journal of Human Genetics, Elsevier (Cell Press), 2017, 101 (5), pp.768 - 788. 〈10.1016/j.ajhg.2017.10.003〉. 〈inserm-01813739〉

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