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De novo mutations in protein kinase genes CAMK2A and CAMK2B cause intellectual disability

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Date: January 11, 2018
Authors:
Addie I. Nesbitt, Ajoy Sarkar, Amber Begtrup, Anne-Sophie Denommé-Pichon, Arie van Haeringen, Aurora Pujol, Avni B. Santani, Ben Distel, Brandon H. Kusako, Bregje W.M. van Bon, Christina Lam, Claudia A. L. Ruivenkamp, Diana S. Johnson, Dorothy K. Grange, Elizabeth A. Sellars, Elizabeth J. Bhoj, Elouan Cherot, Eric Charpentier, Gaëtan Lesca, Geeske M. van Woerden, Geir J. Braathen, George E. Hoganson, Ghayda Mirzaa, Gregory M. Enns, Holly A. F. Stessman, Jane Juusola, Jeff L. Waugh, Jessica Douglas, Jonathan A. Bernstein, Jonathan Berg, Julitta de Bellescize, Katherine B. Bosanko, Katherine L. Helbig, Katrin Hinderhofer, Kimberly Foss, Koen L. I. van Gassen, Kristian Tveten, Laurie A. Robak, Marisa V. Andrews, Matthew Deardorff, Megan T. Cho, Meghan C. Towne, Melissa A. Ploeg, Nagarajan Paramasivam, Paulien A. Terhal, Pierre Lindenbaum, Sandra Mercier, Sharyn Lincoln, Sha Tang, Stephan Sanders, Sébastien Küry, Tabib Dabir, Thomas Besnard, Thomas Simonet, Trine E. Prescott, Ute Moog, Wilfrid Carré, Xénia Latypova, Øystein Lunde Holla, Øyvind Løvold Busk
Journal: American journal of human genetics
Journal Volume: 101
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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.