Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission
Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission
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CSDE1 的破坏性变异与自闭症相关并干扰神经元发育和突触传递
DOI：
10.1126/sciadv.aax2166
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发表时间：
2019-09-01
期刊：
影响因子：
13.6
通讯作者：
Xia, Kun
中科院分区：
文献类型：
--
作者：
Guo, Hui;Li, Ying;Xia, Kun
CSDE 1破坏性突变与自闭症有关。RNA结合蛋白是转录后调节的关键参与者，并与神经发育和神经精神疾病有关。在这里，我们报告了自闭症和相关神经发育障碍患者中CSDE 1（编码一种高度限制的RNA结合蛋白）杂合的可能基因破坏变体的显著负担。对17例患者的分析确定了常见的表型，包括自闭症、智力残疾、语言和运动延迟、癫痫发作、大头畸形和可变的眼部异常。HITS-CLIP显示，Csde 1结合靶点在自闭症相关基因组中富集，尤其是FMRP靶点，并且在神经元发育和突触可塑性相关通路中富集。原代小鼠皮质神经元中Csde 1敲低导致神经突过度生长和异常树突棘形态/突触形成以及突触传递受损，而果蝇中的突变体和敲低实验导致突触生长和突触传递缺陷。我们的研究定义了一种新的自闭症相关综合征，并强调了CSDE 1在突触发育和突触传递中的功能作用。
CSDE1 disruptive mutations are associated with autism. RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity–related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.