A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability.
A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability.
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DOI：
10.7554/elife.32451
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发表时间：
2018-05-22
期刊：
影响因子：
7.7
通讯作者：
Reversade B
中科院分区：
文献类型：
--
作者：
Chia PH;Zhong FL;Niwa S;Bonnard C;Utami KH;Zeng R;Lee H;Eskin A;Nelson SF;Xie WH;Al-Tawalbeh S;El-Khateeb M;Shboul M;Pouladi MA;Al-Raqad M;Reversade B
钙/钙调蛋白依赖的蛋白激酶II(CaMK2)在突触可塑性中发挥重要作用，而突触可塑性是学习和记忆的基础。在这里，我们描述了一种新的隐性神经发育综合征，具有全球发育迟缓、癫痫发作和智能障碍。通过连锁分析和外显子组测序发现，本病定位于染色体5q31.1-q34，由CAMK2A双等位基因突变所致。错义突变p.His477Tyr位于CAMK2a关联域，对其功能和定位至关重要。在生物化学方面，P.His477Tyr突变体存在自我寡聚缺陷，无法组装成多聚体全酶。在体内，CAMK2AH477Y未能修复缺乏UNC-43的线虫的神经元缺陷。UNC-43是人类CAMK2A的直系同源基因。在体外，来自患者IPSCs的神经元显示出严重的突触缺陷。总之，我们的数据表明，CAMK2A的隐性胚系突变会导致人类的神经发育缺陷，并表明功能失调的CaMK2同源基因可能与其他神经疾病有关。每年，一些儿童出生时就患有发育障碍和智力残疾。这些疾病通常是由特定基因的突变引起的。有时，一个基因的两个副本--从父母双方继承的一个--需要发生突变，才能出现症状。这些突变被称为隐性突变。在这里，贾，钟，妮娃等人。在他们的临床护理中，两个兄弟姐妹被诊断出患有一种新的神经疾病，这种疾病影响大脑的发育，并导致频繁的癫痫发作。为了测试这些年轻患者是否分享了可以解释他们病情的基因突变，研究人员分析了这些孩子的DNA，并将结果与他们的父母和健康兄弟姐妹的DNA进行了比较。结果显示，这两名患有这种疾病的儿童遗传了一种名为CAMK2A的基因的隐性突变。该基因编码的蛋白质帮助神经细胞形成连接并相互交流，它已被证明是学习和记忆所必需的。CAMK2A酶由几个相同的亚基组成，形成一个复合体。Chia等人。他们发现，这种突变阻止了这些亚基正确地结合在一起，导致了错误的蛋白质。CAMK2A和其他相关蛋白质对多种动物的大脑健康至关重要。事实上，对秀丽隐杆线虫(一种通常用于研究神经元的蛔虫)的实验证实，儿童遗传的突变确实会导致这些蠕虫出现类似的神经缺陷。综上所述，这些实验表明，这些儿童的疾病是由CAMK2A基因的两个拷贝的突变引起的。对于天生患有遗传性疾病的患者，通常很难准确地确定哪种突变导致了这种特定的疾病。因此，这些发现可以帮助儿科遗传学家认识到这种新定义的综合征，并得出正确的诊断。这些结果也可能成为恢复有缺陷的CAMK2A蛋白活性的研究的起点。更广泛地说，识别对大脑健康发育至关重要的基因可能有助于揭示常见的神经疾病，如癫痫和自闭症。
Calcium/calmodulin-dependent protein kinase II (CAMK2) plays fundamental roles in synaptic plasticity that underlies learning and memory. Here, we describe a new recessive neurodevelopmental syndrome with global developmental delay, seizures and intellectual disability. Using linkage analysis and exome sequencing, we found that this disease maps to chromosome 5q31.1-q34 and is caused by a biallelic germline mutation in CAMK2A. The missense mutation, p.His477Tyr is located in the CAMK2A association domain that is critical for its function and localization. Biochemically, the p.His477Tyr mutant is defective in self-oligomerization and unable to assemble into the multimeric holoenzyme.In vivo, CAMK2AH477Y failed to rescue neuronal defects in C. elegans lacking unc-43, the ortholog of human CAMK2A. In vitro, neurons derived from patient iPSCs displayed profound synaptic defects. Together, our data demonstrate that a recessive germline mutation in CAMK2A leads to neurodevelopmental defects in humans and suggest that dysfunctional CAMK2 paralogs may contribute to other neurological disorders. Each year, some children are born with developmental disorders and intellectual disabilities. These conditions are often caused by mutations in specific genes. Sometimes both copies of a gene – one inherited from each parent – need to be mutated for the symptoms to develop. These mutations are known as recessive mutations. Here, Chia, Zhong, Niwa et al. diagnosed two siblings in their clinical care with a new form of neurological disease that affects the development of the brain and leads to frequent seizures. To test whether the young patients shared a genetic mutation that could explain their condition, the researchers analyzed the DNA of the children and compared the results with the DNA from their parents and healthy siblings. The results showed that the two children with the condition had inherited a recessive mutation in a gene called CAMK2A. The protein this gene encodes helps nerve cells to form connections and communicate with each other, and it has been shown to be essential for learning and memory. The CAMK2A enzyme is made up of several identical subunits that form a complex. Chia et al. discovered that the mutation prevented these subunits from joining together properly, resulting in a faulty protein. CAMK2A and other related proteins are crucial for the health of the brain in a wide range of animals. Indeed, experiments in Caenorhabditis elegans, a roundworm commonly used to study neurons, confirmed that the mutation inherited by the children indeed caused similar neurological defects in the worms. Taken together, these experiments suggest that the children’s condition is caused by the mutation in both copies of the CAMK2A gene. For patients born with inherited diseases, it is often difficult to pinpoint exactly which mutation is responsible for the specific disorder. These findings could therefore help pediatric geneticists recognize this newly defined syndrome and reach the correct diagnoses. These results could also be the starting point for studies that look into restoring the activity of the defective CAMK2A protein.More broadly, identifying genes that are critical for the healthy development of the brain could shed light on common neurological conditions, such as epilepsy and autism.