De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy
De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy
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CDK19 的新变体与涉及智力障碍和癫痫性脑病的综合征有关。
DOI：
10.1016/j.ajhg.2020.04.001
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发表时间：
2020-05-07
影响因子：
9.8
通讯作者：
Xiao, Bo
中科院分区：
文献类型：
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作者：
Chung, Hyung-lok;Mao, Xiao;Xiao, Bo
我们确定了三个不相关的个体与从头错义变异的CDK19，编码细胞周期蛋白依赖性激酶蛋白家族成员，主要调节基因转录。这些个体表现为张力减退、全面发育迟缓、癫痫性脑病和畸形特征。CDK19在脊椎动物和无脊椎动物模式生物之间是保守的，但目前尚不知道CDK19的异常与人类疾病相关。CDK19的蝇同源物Cdk8的缺失导致幼虫致死，这被人CDK19参考cDNA的表达抑制。相反，在受影响的个体中鉴定的CDK19 p.Tyr32His和p.Thr196Ala变体不能挽救Cdk8的丢失，并且表现为无效等位基因。此外，果蝇中神经元RNAi介导的Cdk8敲低导致半致死性。少数羽化苍蝇表现出严重的癫痫发作和寿命缩短。两种表型均被CDK19参比cDNA的适度表达完全抑制，但不被两种变体的表达完全抑制。最后，Cdk8的损失导致幼虫神经肌肉接头（NMJ）的结和突触的明显损失。总之，我们的研究结果表明，人类CDK19完全取代了果蝇中Cdk8的功能，人类疾病相关的CDK19变体表现为强烈的功能丧失变体，有害的CDK19变体是综合征性神经发育障碍的基础。
We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that predominantly regulates gene transcription. These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features. CDK19 is conserved between vertebrate and invertebrate model organisms, but currently abnormalities in CDK19 are not known to be associated with a human disorder. Loss of Cdk8, the fly homolog of CDK19, causes larval lethality, which is suppressed by expression of human CDK19 reference cDNA. In contrast, the CDK19 p.Tyr32His and p.Thr196Ala variants identified in the affected individuals fail to rescue the loss of Cdk8 and behave as null alleles. Additionally, neuronal RNAi-mediated knockdown of Cdk8 in flies results in semi-lethality. The few eclosing flies exhibit severe seizures and a reduced lifespan. Both phenotypes are fully suppressed by moderate expression of the CDK19 reference cDNA but not by expression of the two variants. Finally, loss of Cdk8 causes an obvious loss of boutons and synapses at larval neuromuscular junctions (NMJs). Together, our findings demonstrate that human CDK19 fully replaces the function of Cdk8 in the fly, the human disease-associated CDK19 variants behave as strong loss-of-function variants, and deleterious CDK19 variants underlie a syndromic neurodevelopmental disorder.