CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy
CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy
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DOI：
10.1002/humu.23270
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发表时间：
2017-08-01
期刊：
影响因子：
3.9
通讯作者：
Bienvenu, Thierry
中科院分区：
文献类型：
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作者：
Poirier, Karine;Hubert, Laurence;Bienvenu, Thierry
从头突变是大脑发育相关疾病的常见原因。我们报告了两名被诊断为智力障碍（ID）患者的筛查结果，使用外显子组测序来识别新的致病突变。在两个患者-父母三人组中进行了外显子组测序，以鉴定从头变异。还进行了计算机模拟和表达研究，以评估这些变体的功能后果。两名患者均出现发育迟缓并伴有轻微面部畸形。其中一名患者出现耐药性肌阵挛性癫痫。我们在编码酪氨酸激酶 2 (CK2) 亚基的 CSNK2B 基因中鉴定了两个从头剪接变体 (c.175+2T>G；c.367+2T>C)。 CK2 是一种普遍表达的激酶，在大脑中以高水平存在，并且似乎具有组成性活性。受影响的成纤维细胞中的 mRNA 转录物异常且显着减少，并且很可能产生截短的蛋白质。考虑到先前在患有神经发育障碍和畸形特征的患者中发现了编码CK2亚基的CSNK2A1突变，我们的研究证实了蛋白激酶CK2在大脑中发挥着重要作用，并表明编码该亚基的CSNK2是一种新型ID基因。这项研究为越来越多的 ID 和癫痫致病基因和候选基因增加了知识，并强调 CSNK2B 作为神经发育障碍的新基因。
De novo mutations are a frequent cause of disorders related to brain development. We report the results from the screening of two patients diagnosed with intellectual disability (ID) using exome sequencing to identify new causative de novo mutations. Exome sequencing was conducted in two patient-parent trios to identify de novo variants. In silico and expression studies were also performed to evaluate the functional consequences of these variants. The two patients presented developmental delay with minor facial dysmorphy. One of them presented pharmacoresistant myoclonic epilepsy. We identified two de novo splice variants (c.175+2T>G; c.367+2T>C) in the CSNK2B gene encoding the subunit of the Caseine kinase 2 (CK2). CK2 is a ubiquitously expressed kinase that is present in high levels in brain and it appears to be constitutively active. The mRNA transcripts were abnormal and significantly reduced in affected fibroblasts and most likely produced truncated proteins. Taking into account that mutations in CSNK2A1, encoding the subunit of CK2, were previously identified in patients with neurodevelopmental disorders and dysmorphic features, our study confirmed that the protein kinase CK2 plays a major role in brain, and showed that CSNK2, encoding the subunit, is a novel ID gene. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy, and highlights CSNK2B as a new gene for neurodevelopmental disorders.