Stress granules (SGs) are cytoplasmic assemblies in response to a variety of stressors. We report a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in UBAP2L , which encodes an essential regulator of SG assembly. Ubap2l haploinsufficiency in mouse led to social and cognitive impairments accompanied by disrupted neurogenesis and reduced SG formation during early brain development. On the basis of data from 40,853 individuals with NDDs, we report a nominally significant excess of de novo variants within 29 genes that are not implicated in NDDs, including 3 essential genes ( G3BP1 , G3BP2 , and UBAP2L ) in the core SG interaction network. We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as CAPRIN1 , disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.

中文翻译：

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调节应激颗粒组装的基因的从头变异与神经发育障碍相关


应激颗粒（SG）是响应各种应激源的细胞质组件。我们报告了一种新的神经发育障碍（NDD），其共同特征是语言问题、智力障碍和行为问题，这些问题是由 UBAP2L 中可能从头开始的基因破坏性变异引起的，UBAP2L 编码 SG 组装的重要调节因子。小鼠中的 Ubap2l 单倍体不足会导致社交和认知障碍，并伴有早期大脑发育过程中神经发生中断和 SG 形成减少。根据 40,853 名 NDD 患者的数据，我们报告了 29 个与 NDD 无关的基因中名义上显着过量的从头变异，其中包括核心 SG 相互作用网络中的 3 个必需基因（ G3BP1 、 G3BP2 和 UBAP2L ）。我们验证了新发现的 NDD 基因（例如 CAPRIN1）中与 NDD 相关的从头变异，会破坏核心 SG 网络的相互作用并干扰 SG 的形成。总之，我们的研究结果表明了 NDD 中常见的 SG 病理学。