CUL3 forms Cullin-Ring ubiquitin ligases (CRL) with Ring-box protein and BTB-adaptor proteins. A variety of BTB-adaptor proteins have been reported to interact with the N-terminus of CUL3, which makes it possible to recognize various substrates for degradation. Regarding the association of CUL3 with neurodevelopmental disorders, a recent study reported three patients with global developmental delay, who carried de novo variants in CUL3. Here, we describe a novel de novo CUL3 variant (c.158G > A, p.Ser53Asn) identified in a patient with global developmental delay, who presented some novel dysmorphic features, including macrocephaly, characteristic facial features, and cutis marmorata. Immunoprecipitation and immunoblot analyses identified significantly weaker binding ability to some BTB proteins in CUL3-S53N compared to wild-type. Interestingly, label-free quantification proteomics analysis of samples immunoprecipitated by CUL3-S53N showed a significantly decreased interaction with some BTB proteins, while almost equal interaction or significantly increased interaction was observed with other BTB proteins. The binding between CUL3 and BTB proteins is essential for CRL substrate recognition, and alteration of their interaction is thought to result in the quantitative alteration in substrate proteins. It is possible that the difference of dysmorphic features between the present case and previously reported cases is caused by the distinctive effect of each CUL3 variant on substrate proteins. The clinical information of the present case will expand the picture of CUL3-related global developmental disorders, and subsequent cell biological analysis of the novel mutation will provide insight into the underlying molecular mechanism of how CUL3 pathogenic variants cause neurological disorders.

CUL3 与环盒蛋白和 BTB 接头蛋白形成 Cullin-Ring 泛素连接酶 (CRL)。据报道，多种 BTB 接头蛋白与 CUL3 的 N 端相互作用，这使得识别各种降解底物成为可能。关于 CUL3 与神经发育障碍的关联，最近的一项研究报告了三名全身发育迟缓的患者，他们携带CUL3 中的从头变异。在这里，我们描述了一个新的从头CUL3变异 (c.158G > A, p.Ser53Asn) 在一名全身发育迟缓的患者身上发现，他呈现出一些新的畸形特征，包括大头畸形、特征性面部特征和角质层。免疫沉淀和免疫印迹分析发现，与野生型相比，CUL3-S53N 中某些 BTB 蛋白的结合能力明显较弱。有趣的是，通过 CUL3-S53N 免疫沉淀的样品的无标记定量蛋白质组学分析表明，与某些 BTB 蛋白的相互作用显着降低，而与其他 BTB 蛋白的相互作用几乎相等或显着增加。CUL3 和 BTB 蛋白之间的结合对于 CRL 底物识别至关重要，并且它们相互作用的改变被认为会导致底物蛋白的定量改变。底物蛋白上的CUL3变体。本病例的临床信息将扩大与 CUL3 相关的全球发育障碍的图景，随后对新突变的细胞生物学分析将提供对CUL3致病变异如何导致神经系统疾病的潜在分子机制的深入了解。