De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders

被引：26

作者：

Jia, Xiangbin ^{[1
,2
]}

Zhang, Shujie ^{[3
,4
,5
]}

Tan, Senwei ^{[1
,2
]}

Du, Bing ^{[1
,2
]}

He, Mei ^{[1
,2
,6
]}

Qin, Haisong ^{[3
]}

Chen, Jia ^{[1
,2
]}

Duan, Xinyu ^{[7
]}

Luo, Jingsi ^{[3
]}

Chen, Fei ^{[3
]}

Ouyang, Luping ^{[3
]}

Wang, Jian ^{[4
,5
]}

Chen, Guodong ^{[1
,2
]}

Yu, Bin ^{[1
,2
]}

Zhang, Ge ^{[1
,2
]}

Zhang, Zimin ^{[1
,2
]}

Lyu, Yongqing ^{[1
,2
]}

Huang, Yi ^{[8
]}

Jiao, Jian ^{[8
]}

Chen, Jin Yun Helen ^{[9
]}

Swoboda, Kathryn J. ^{[10
]}

Agolini, Emanuele ^{[11
]}

Novelli, Antonio ^{[11
]}

Leoni, Chiara ^{[12
]}

Zampino, Giuseppe ^{[12
,13
,14
,15
]}

Cappuccio, Gerarda ^{[16
,17
]}

Brunetti-Pierri, Nicola ^{[16
,17
]}

Gerard, Benedicte ^{[18
]}

Ginglinger, Emmanuelle ^{[19
]}

Richer, Julie ^{[20
]}

McMillan, Hugh ^{[21
]}

White-Brown, Alexandre ^{[22
]}

Hoekzema, Kendra ^{[23
]}

Bernier, Raphael A. ^{[24
]}

Kurtz-Nelson, Evangeline C. ^{[25
]}

Earl, Rachel K. ^{[24
]}

Meddens, Claartje ^{[26
,27
]}

Alders, Marielle ^{[28
]}

Fuchs, Meredith ^{[29
]}

Caumes, Roseline ^{[30
]}

Brunelle, Perrine ^{[31
]}

Smol, Thomas ^{[31
]}

Kuehl, Ryan ^{[32
]}

Day-Salvatore, Debra-Lynn ^{[32
]}

Monaghan, Kristin G. ^{[33
]}

Morrow, Michelle M. ^{[33
]}

Eichler, Evan E. ^{[23
,34
]}

Hu, Zhengmao ^{[1
,2
]}

Yuan, Ling ^{[1
,2
]}

Tan, Jieqiong ^{[1
,2
]}

机构：

[1] Cent South Univ, Ctr Med Genet, Sch Life Sci, Changsha 410078, Hunan, Peoples R China

[2] Cent South Univ, Sch Life Sci, Hunan Key Lab Med Genet, Changsha 410078, Hunan, Peoples R China

[3] Maternal & Child Hlth Hosp Guangxi Zhuang Autonom, Birth Defects Prevent & Control Inst Guangxi Zhua, Genet & Metab Cent Lab, Nanning 530003, Peoples R China

[4] Shanghai Jiao Tong Univ, Shanghai Childrens Med Ctr, Sch Med, Dept Med Genet, Shanghai 200000, Peoples R China

[5] Shanghai Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr, Mol Diagnost Lab, Shanghai 200000, Peoples R China

[6] Hunan Prov Maternal & Child Hlth Care Hosp, NHC Key Lab Birth Defect Res & Prevent, Changsha, Hunan, Peoples R China

[7] Army Med Univ, Daping Hosp, Dept Pediat, Chongqing, Peoples R China

[8] Sichuan Univ, West China Hosp, Mental Hlth Ctr, Chengdu 610000, Peoples R China

[9] Massachusetts Gen Brigham, Dept Neurol, Massachusetts Gen Hosp, Neurogenet Unit, Boston, MA 02114 USA

[10] Harvard Med Sch, Ctr Genom Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA

[11] Bambino Gesu Pediat Hosp, Lab Med Genet, IRCCS, I-00165 Rome, Italy

[12] Fdn Policlin Univ A Gemelli IRCCS, Ctr Rare Dis & Birth Defects, Dept Woman & Child Hlth & Publ Hlth, I-00168 Rome, Italy

[13] Univ Cattolica Sacro Cuore, Fac Med & Surg, I-00168 Rome, Italy

[14] Fdn Policlin Univ Agostino Gemelli, Dipartimento Sci Salute Donna & Bambino, Rome, Italy

[15] Univ Cattolica S Cuore, Dipartimento Sci Vita & Sanita Pubbl, Rome, Italy

[16] Telethon Inst Genet & Med TIGEM, Pozzuoli, Italy

[17] Univ Naples Federico II, Dept Translat Med, Naples, Italy

[18] Hop Univ Strasbourg, Inst Genet Med Alsace IGMA, Lab Diagnost Genet, Strasbourg, Alsace, France

[19] Ctr Hosp Mulhouse, Serv Genet, Mulhouse, Alsace, France

[20] Childrens Hosp Eastern Ontario, Dept Med Genet, Ottawa, ON, Canada

[21] McGill Univ, Montreal Childrens Hosp, Dept Pediat Neurol & Neurosurg, Montreal, PQ, Canada

[22] Univ Ottawa, Childrens Hosp Eastern Ontario Res Inst, Ottawa, ON, Canada

[23] Univ Washington, Dept Genome Sci, Sch Med, Seattle, WA 98195 USA

[24] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA

[25] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA

[26] Amsterdam Univ Med Ctr, Dept Clin Genet, Amsterdam, Netherlands

[27] Univ Med Ctr Utrecht, Dept Paediat, Utrecht, Netherlands

[28] Univ Amsterdam, Amsterdam Univ Med Ctr, Amsterdam Reprod & Dev Res Inst, Dept Human Genet, Amsterdam, Netherlands

[29] Pediat & Genet, Alpharetta, GA 30005 USA

[30] CHU Lille, Clin Genet, F-59000 Lille, France

[31] Univ Lille, Inst Genet Med, CHU Lille, ULR7364 RADEME, F-59000 Lille, France

[32] St Peters Univ Hosp, Dept Med Genet & Genom Med, New Brunswick, NJ 08901 USA

[33] GeneDx, Gaithersburg, MD 20877 USA

[34] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA

[35] Chinese Acad Sci, CAS Ctr Excellence Brain Sci & Intelligences Tech, Shanghai 200000, Peoples R China

[36] Univ South China, Hengyang Med Sch, Hengyang, Peoples R China

[37] Harvard Med Sch, Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA

[38] Hunan Key Lab Anim Models Human Dis, Changsha 410078, Hunan, Peoples R China

来源：

SCIENCE ADVANCES | 2022年 / 8卷 / 33期

基金：

中国国家自然科学基金;

关键词：

AUTISM SPECTRUM DISORDER; MESSENGER-RNA DECAY; BRAIN-DEVELOPMENT; MUTATIONS; FRAMEWORK; GENETICS; GENOMICS; BEHAVIOR; MODELS;

D O I：

10.1126/sciadv.abo7112

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Stress granules (SGs) are cytoplasmic assemblies in response to a variety of stressors. We report a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in UBAP2L, which encodes an essential regulator of SG assembly. Ubap2l haploinsufficiency in mouse led to social and cognitive impairments accompanied by disrupted neurogenesis and reduced SG formation during early brain development. On the basis of data from 40,853 individuals with NDDs, we report a nominally significant excess of de novo variants within 29 genes that are not implicated in NDDs, including 3 essential genes (G3BP1, G36P2, and UBAP2L) in the core SG interaction network. We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as CAPRlNI, disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.

引用

页数：16

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