De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability
De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability
复制标题
DOI：
10.1016/j.ajhg.2017.10.003
复制
发表时间：
2017-11-02
影响因子：
9.8
通讯作者：
Mercier, Sandra
中科院分区：
文献类型：
--
作者：
Kury, Sebastien;van Woerden, Geeske M.;Mercier, Sandra
钙/钙调蛋白依赖的蛋白激酶II(CaMK2)是最早被证明对小鼠正常学习和突触可塑性是必需的蛋白质之一，但它对人脑发育的需求尚未确定。通过一项基于全外显子组测序方法的多中心协作研究，我们在24名无关的智力残疾个体中发现了19个极其罕见的从头CAMK2A或CAMK2B变异。评估了突变对CaMK2功能和神经元迁移的影响。对于CAMK2A和CAMK2B，我们发现了减少或增加Thr286/Thr287处CaMK2自动磷酸化的突变。我们进一步发现，所有影响自动磷酸化的突变也影响神经元迁移，强调了严格调控的CaMK2自动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脑功能中的重要性，并扩大了谷氨酸能信号通路关键成员变异引起的疾病的表型谱。
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.