De Novo Mutations of CCNK Cause a Syndromic Neurodevelopmental Disorder with Distinctive Facial Dysmorphism
De Novo Mutations of CCNK Cause a Syndromic Neurodevelopmental Disorder with Distinctive Facial Dysmorphism
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CCNK 的从头突变导致综合征性神经发育障碍，伴有独特的面部畸形
DOI：
10.1016/j.ajhg.2018.07.019
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发表时间：
2018-09-06
影响因子：
9.8
通讯作者：
Yu, Yongguo
中科院分区：
文献类型：
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作者：
Fan, Yanjie;Yin, Wu;Yu, Yongguo
神经发育是一个转录协调的过程。细胞周期蛋白K是由CCNK编码的转录调节因子，被认为在RNA聚合酶II介导的活动中起关键作用。然而，CCNK功能障碍与遗传性疾病无关。在这项研究中，我们确定了三个不相关的个人窝藏从头杂合拷贝数丢失的CCNK在一个重叠的14q32.3区域和一个人窝藏从头非同义变异CCNK c.331A>G（p.Lys111Glu）。这四个人，虽然来自不同的种族背景，但有一个共同的表型发育迟缓和智力残疾（DD/ID），语言缺陷，和独特的面部畸形，包括高发际线，间距过大，细眉毛，畸形耳朵，宽鼻梁和鼻尖，窄下巴。在斑马鱼幼鱼中的功能测定显示，Ccnk敲低导致脑发育缺陷、小眼睛和卷曲的脊髓。这些缺陷被编码CNK的野生型mRNA部分挽救，但不是具有鉴定的可能致病变体c.331A>G的mRNA，支持CNK变体在神经发育障碍中的因果作用。总之，我们报告了一个综合征性神经发育障碍与DD/ID和面部特征所造成的CCNK的变化，可能通过单倍不足的机制。
Neurodevelopment is a transcriptionally orchestrated process. Cyclin K, a regulator of transcription encoded by CCNK, is thought to play a critical role in the RNA polymerase II-mediated activities. However, dysfunction of CCNK has not been linked to genetic disorders. In this study, we identified three unrelated individuals harboring de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region and one individual harboring a de novo nonsynonymous variant c.331A>G (p.Lys111Glu) in CCNK. These four individuals, though from different ethnic backgrounds, shared a common phenotype of developmental delay and intellectual disability (DD/ID), language defects, and distinctive facial dysmorphism including high hairline, hypertelorism, thin eyebrows, dysmorphic ears, broad nasal bridge and tip, and narrow jaw. Functional assay in zebrafish larvae showed that Ccnk knockdown resulted in defective brain development, small eyes, and curly spinal cord. These defects were partially rescued by wild-type mRNA coding CCNK but not the mRNA with the identified likely pathogenic variant c.331A>G, supporting a causal role of CCNK variants in neurodevelopmental disorders. Taken together, we reported a syndromic neurodevelopmental disorder with DD/ID and facial characteristics caused by CCNK variations, possibly through a mechanism of haploinsufficiency.