A novel missense variant in CUL3 shows altered binding ability to BTB-adaptor proteins leading to diverse phenotypes of CUL3-related disorders
A novel missense variant in CUL3 shows altered binding ability to BTB-adaptor proteins leading to diverse phenotypes of CUL3-related disorders
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DOI：
10.1038/s10038-020-00868-9
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发表时间：
2020-10
影响因子：
3.5
通讯作者：
Kohji Kato;F. Miya;Yasuyoshi Oka;S. Mizuno;S. Saitoh
中科院分区：
文献类型：
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作者：
Kohji Kato;F. Miya;Yasuyoshi Oka;S. Mizuno;S. Saitoh
CUL3与Ring-box蛋白和BTB-adaptor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，这使得识别各种底物进行降解成为可能。关于CUL3与神经发育障碍的关系，最近的一项研究报道了3例全身发育迟缓患者，他们携带CUL3的新生变异。在这里，我们描述了一种新的de novocul3变异（c.158G > a, p.Ser53Asn），发现于一名整体发育迟缓的患者，该患者表现出一些新的畸形特征，包括大头畸形、特征面部特征和皮肤凹陷。免疫沉淀和免疫印迹分析发现，CUL3-S53N与某些BTB蛋白的结合能力明显弱于野生型。有趣的是，CUL3-S53N免疫沉淀样品的无标记定量蛋白质组学分析显示，CUL3-S53N与某些BTB蛋白的相互作用显著降低，而与其他BTB蛋白的相互作用几乎相等或显著增加。CUL3和BTB蛋白之间的结合对于CRL底物识别至关重要，它们相互作用的改变被认为会导致底物蛋白的定量改变。本病例和以前报道的病例之间畸形特征的差异可能是由每个cul3变异对底物蛋白的不同作用引起的。本病例的临床信息将扩大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为cul3致病变异如何导致神经系统疾病的潜在分子机制提供见解。
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 inCUL3. Here, we describe a novel de novoCUL3variant (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 eachCUL3variant 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 howCUL3pathogenic variants cause neurological disorders.