RAD21 Mutations Cause a Human Cohesinopathy

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• 作者：Matthew  ; A. Deardorff¹ ; ² ; ^{deardorff@email.chop.edu} ; Jonathan  ; J. Wilde¹ ; Melanie Albrecht³ ; Emma Dickinson⁴ ; Stephanie Tennstedt⁵ ; Diana Braunholz³ ; Maren Mö ; nnich⁴ ; Yuqian Yan⁶ ; Weizhen Xu³ ; ⁷ ; Mar&#237 ; a  ; Concepcion Gil-Rodr&#237 ; guez³ ; ⁸ ; Dinah Clark¹ ; Hakon Hakonarson¹ ; ² ; ⁹ ; Sara Halbach¹⁰ ; Laura  ; Daniela Michelis¹ ; Abhinav Rampuria¹ ; Eva Rossier¹¹ ; Stephanie Spranger¹² ; Lionel Van  ; Maldergem¹³ ; Sally  ; Ann Lynch¹⁴ ; Gabriele Gillessen-Kaesbach³ ; Hermann-Josef Lü ; decke¹⁵ ; Robert  ; G. Ramsay⁶ ; ¹⁶ ; Michael  ; J. McKay¹⁷ ; ¹⁸ ; Ian  ; D. Krantz¹ ; ² ; Huiling Xu⁶ ; ¹⁶ ; Julia  ; A. Horsfield⁴ ; Frank  ; J. Kaiser³ ; ^{frank.kaiser@uk-sh.de}
• 刊名：The American Journal of Human Genetics
• 出版年：2012
• 期刊代码：P22_00029297
• 类别：bio
• 出版时间：8 June, 2012
• 卷：90
• 期：6
• 页码：1014-1027
• 文件大小：1084 K

摘要

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 鈥渃ohesinopathy.鈥?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.