Küry Sébastien, van Woerden Geeske M, Besnard Thomas, Proietti Onori Martina, Latypova Xénia, Towne Meghan C, Cho Megan T, Prescott Trine E, Ploeg Melissa A, Sanders Stephan, Stessman Holly A F, Pujol Aurora, Distel Ben, Robak Laurie A, Bernstein Jonathan A, Denommé-Pichon Anne-Sophie, Lesca Gaëtan, Sellars Elizabeth A, Berg Jonathan, Carré Wilfrid, Busk Øyvind Løvold, van Bon Bregje W M, Waugh Jeff L, Deardorff Matthew, Hoganson George E, Bosanko Katherine B, Johnson Diana S, Dabir Tabib, Holla Øystein Lunde, Sarkar Ajoy, Tveten Kristian, de Bellescize Julitta, Braathen Geir J, Terhal Paulien A, Grange Dorothy K, van Haeringen Arie, Lam Christina, Mirzaa Ghayda, Burton Jennifer, Bhoj Elizabeth J, Douglas Jessica, Santani Avni B, Nesbitt Addie I, Helbig Katherine L, Andrews Marisa V, Begtrup Amber, Tang Sha, van Gassen Koen L I, Juusola Jane, Foss Kimberly, Enns Gregory M, Moog Ute, Hinderhofer Katrin, Paramasivam Nagarajan, Lincoln Sharyn, Kusako Brandon H, Lindenbaum Pierre, Charpentier Eric, Nowak Catherine B, Cherot Elouan, Simonet Thomas, Ruivenkamp Claudia A L, Hahn Sihoun, Brownstein Catherine A, Xia Fan, Schmitt Sébastien, Deb Wallid, Bonneau Dominique, Nizon Mathilde, Quinquis Delphine, Chelly Jamel, Rudolf Gabrielle, Sanlaville Damien, Parent Philippe, Gilbert-Dussardier Brigitte, Toutain Annick, Sutton Vernon R, Thies Jenny, Peart-Vissers Lisenka E L M, Boisseau Pierre, Vincent Marie, Grabrucker Andreas M, Dubourg Christèle, Tan Wen-Hann, Verbeek Nienke E, Granzow Martin, Santen Gijs W E, Shendure Jay, Isidor Bertrand, Pasquier Laurent, Redon Richard, Yang Yaping, State Matthew W, Kleefstra Tjitske, Cogné Benjamin, Petrovski Slavé, Retterer Kyle, Eichler Evan E, Rosenfeld Jill A, Agrawal Pankaj B, Bézieau Stéphane, Odent Sylvie, Elgersma Ype, Mercier Sandra
CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes Cedex 1, France.
Department of Neuroscience, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands; ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands.
Am J Hum Genet. 2017 Nov 2;101(5):768-788. doi: 10.1016/j.ajhg.2017.10.003.
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.
钙/钙调蛋白依赖性蛋白激酶II（CAMK2）是最早被证明对小鼠正常学习和突触可塑性至关重要的蛋白质之一，但其对人类大脑发育的必要性尚未确定。通过一项基于全外显子测序方法的多中心合作研究，我们在24名无关的智力残疾个体中鉴定出19个极其罕见的新发CAMK2A或CAMK2B变异。评估了这些变异对CAMK2功能和神经元迁移的影响。对于CAMK2A和CAMK2B，我们都鉴定出了可降低或增加Thr286/Thr287位点CAMK2自身磷酸化的突变。我们进一步发现，所有影响自身磷酸化的突变也影响神经元迁移，这突出了严格调控的CAMK2自身磷酸化在神经元功能和神经发育中的重要性。我们的数据证实了CAMK2A和CAMK2B及其自身磷酸化在人类脑功能中的重要性，并扩展了由谷氨酸能信号通路关键因子变异引起的疾病的表型谱。
