The ubiquitin-proteasome system is the principal system for protein degradation mediated by ubiquitination and is involved in various cellular processes. Cullin-RING ligases (CRL) are one class of E3 ubiquitin ligases that mediate polyubiquitination of specific target proteins, leading to decomposition of the substrate. Cullin 3 (CUL3) is a member of the Cullin family proteins, which act as scaffolds of CRL. Here we describe three cases of global developmental delays, with or without epilepsy, who had de novo CUL3 variants. One missense variant c.854T>C, p.(Val285Ala) and two frameshift variants c.137delG, p.(Arg46Leufs*32) and c.1239del, p.(Asp413Glufs*42) were identified by whole-exome sequencing. The Val285 residue located in the Cullin N-terminal domain and p.Val285Ala CUL3 mutant showed significantly weaker interactions to the BTB domain proteins than wild-type CUL3. Our findings suggest that de novo CUL3 variants may cause structural instability of the CRL complex and impairment of the ubiquitin-proteasome system, leading to diverse neuropsychiatric disorders.

中文翻译：

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CUL3中的从头变异与有或没有婴儿痉挛的全球发育延迟有关。

泛素-蛋白酶体系统是由泛素化介导的蛋白质降解的主要系统，并参与各种细胞过程。Cullin-ring连接酶（CRL）是一类E3泛素连接酶，可介导特定靶蛋白的多泛素化作用，从而导致底物分解。Cullin 3（CUL3）是Cullin家族蛋白的成员，该蛋白充当CRL的支架。在这里，我们描述了三例具有新生CUL3变异的有或没有癫痫的全球发育延迟的病例。通过全外显子测序鉴定出一个错义变体c.854T> C，p。（Val285Ala）和两个移码变体c.137delG，p。（Arg46Leufs * 32）和c.1239del，p。（Asp413Glufs * 42）。Val285残基位于Cullin N末端结构域和p。与野生型CUL3相比，Val285Ala CUL3突变体与BTB结构域蛋白的相互作用明显弱。我们的发现表明，从头CUL3变异可能会导致CRL复合物的结构不稳定性和泛素-蛋白酶体系统的损伤，从而导致多种神经精神疾病。