| Literature DB >> 29100089 |
Sébastien Küry1, Geeske M van Woerden2, Thomas Besnard3, Martina Proietti Onori2, Xénia Latypova3, Meghan C Towne4, Megan T Cho5, Trine E Prescott6, Melissa A Ploeg2, Stephan Sanders7, Holly A F Stessman8, Aurora Pujol9, Ben Distel10, Laurie A Robak11, Jonathan A Bernstein12, Anne-Sophie Denommé-Pichon13, Gaëtan Lesca14, Elizabeth A Sellars15, Jonathan Berg16, Wilfrid Carré17, Øyvind Løvold Busk6, Bregje W M van Bon18, Jeff L Waugh19, Matthew Deardorff20, George E Hoganson21, Katherine B Bosanko15, Diana S Johnson22, Tabib Dabir23, Øystein Lunde Holla6, Ajoy Sarkar24, Kristian Tveten6, Julitta de Bellescize25, Geir J Braathen6, Paulien A Terhal26, Dorothy K Grange27, Arie van Haeringen28, Christina Lam29, Ghayda Mirzaa30, Jennifer Burton21, Elizabeth J Bhoj31, Jessica Douglas32, Avni B Santani33, Addie I Nesbitt34, Katherine L Helbig35, Marisa V Andrews27, Amber Begtrup5, Sha Tang36, Koen L I van Gassen26, Jane Juusola5, Kimberly Foss37, Gregory M Enns12, Ute Moog38, Katrin Hinderhofer38, Nagarajan Paramasivam39, Sharyn Lincoln32, Brandon H Kusako32, Pierre Lindenbaum40, Eric Charpentier40, Catherine B Nowak32, Elouan Cherot17, Thomas Simonet25, Claudia A L Ruivenkamp28, Sihoun Hahn29, Catherine A Brownstein4, Fan Xia41, Sébastien Schmitt3, Wallid Deb3, Dominique Bonneau13, Mathilde Nizon3, Delphine Quinquis3, Jamel Chelly42, Gabrielle Rudolf43, Damien Sanlaville14, Philippe Parent44, Brigitte Gilbert-Dussardier45, Annick Toutain46, Vernon R Sutton47, Jenny Thies48, Lisenka E L M Peart-Vissers18, Pierre Boisseau3, Marie Vincent3, Andreas M Grabrucker49, Christèle Dubourg17, Wen-Hann Tan32, Nienke E Verbeek26, Martin Granzow38, Gijs W E Santen28, Jay Shendure50, Bertrand Isidor3, Laurent Pasquier51, Richard Redon40, Yaping Yang41, Matthew W State7, Tjitske Kleefstra18, Benjamin Cogné3, Slavé Petrovski52, Kyle Retterer5, Evan E Eichler50, Jill A Rosenfeld11, Pankaj B Agrawal53, Stéphane Bézieau54, Sylvie Odent51, Ype Elgersma55, Sandra Mercier3.
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.Entities:
Keywords: AMPAR; CAMK2; CAMK2A; CAMK2B; NMDAR; de novo mutations; intellectual disability; synaptic plasticity
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Year: 2017 PMID： 29100089 PMCID： PMC5673671 DOI： 10.1016/j.ajhg.2017.10.003
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025