RAD21 Mutations Cause a Human Cohesinopathy
RAD21 Mutations Cause a Human Cohesinopathy
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DOI：
10.1016/j.ajhg.2012.04.019
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发表时间：
2012-06-08
影响因子：
9.8
通讯作者：
Kaiser, Frank J.
中科院分区：
文献类型：
--
作者：
Deardorff, Matthew A.;Wilde, Jonathan J.;Kaiser, Frank J.
进化上保守的内聚蛋白复合物最初被描述为在有丝分裂和减数分裂过程中调节姐妹染色单体内聚的作用。内聚蛋白及其调节蛋白与多种人类发育障碍有关，包括科内利亚·德·兰格综合征（CdLS）和罗伯茨综合征。在这里，我们表明人类整体内聚蛋白结构蛋白RAD21的突变导致先天性表型与“内聚病”一致。患有RAD21突变的儿童表现出生长迟缓、轻微的骨骼异常和面部特征，这些特征与CdLS患者的发现重叠。值得注意的是，与NIPBL、SMC1A或SMC3突变的儿童不同，这些个体的认知障碍比经典CdLS患者要轻得多。在斑马鱼模型中，这些突变在RAD21与其他内聚蛋白STAG2和SMC1A的界面上起作用，损害细胞DNA损伤反应，并破坏转录。我们的数据表明，与功能丧失突变相比，显性错义突变导致更严重的功能缺陷，并导致更差的结构和认知临床表现。这些结果强调了RAD21在真核生物中的重要作用，并强调了进一步了解内聚蛋白在人类发育中的作用的必要性。
The evolutionarily conserved cohesin complex was originally described for its role in regulating sister-chromatid cohesion during mitosis and meiosis. Cohesin and its regulatory proteins have been implicated in several human developmental disorders, including Cornelia de Lange (CdLS) and Roberts syndromes. Here we show that human mutations in the integral cohesin structural protein RAD21 result in a congenital phenotype consistent with a "cohesinopathy." Children with RAD21 mutations display growth retardation, minor skeletal anomalies, and facial features that overlap findings in individuals with CdLS. Notably, unlike children with mutations in NIPBL, SMC1A, or SMC3, these individuals have much milder cognitive impairment than those with classical CdLS. Mechanistically, these mutations act at the RAD21 interface with the other cohesin proteins STAG2 and SMC1A, impair cellular DNA damage response, and disrupt transcription in a zebrafish model. Our data suggest that, compared to loss-of-function mutations, dominant missense mutations result in more severe functional defects and cause worse structural and cognitive clinical findings. These results underscore the essential role of RAD21 in eukaryotes and emphasize the need for further understanding of the role of cohesin in human development.