TY - JOUR
T1 - De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders
AU - Jia, Xiangbin
AU - Zhang, Shujie
AU - Tan, Senwei
AU - Du, Bing
AU - He, Mei
AU - Qin, Haisong
AU - Chen, Jia
AU - Duan, Xinyu
AU - Luo, Jingsi
AU - Chen, Fei
AU - Ouyang, Luping
AU - Wang, Jian
AU - Chen, Guodong
AU - Yu, Bin
AU - Zhang, Ge
AU - Zhang, Zimin
AU - Lyu, Yongqing
AU - Huang, Yi
AU - Jiao, Jian
AU - Chen, Jin Yun Helen
AU - Swoboda, Kathryn J.
AU - Agolini, Emanuele
AU - Novelli, Antonio
AU - Leoni, Chiara
AU - Zampino, Giuseppe
AU - Cappuccio, Gerarda
AU - Brunetti-Pierri, Nicola
AU - Gerard, Benedicte
AU - Ginglinger, Emmanuelle
AU - Richer, Julie
AU - McMillan, Hugh
AU - White-Brown, Alexandre
AU - Hoekzema, Kendra
AU - Bernier, Raphael A.
AU - Kurtz-Nelson, Evangeline C.
AU - Earl, Rachel K.
AU - Meddens, Claartje
AU - Alders, Marielle
AU - Fuchs, Meredith
AU - Caumes, Roseline
AU - Brunelle, Perrine
AU - Smol, Thomas
AU - Kuehl, Ryan
AU - Day-Salvatore, Debra Lynn
AU - Monaghan, Kristin G.
AU - Morrow, Michelle M.
AU - Eichler, Evan E.
AU - Hu, Zhengmao
AU - Yuan, Ling
AU - Tan, Jieqiong
N1 - Funding Information:
This study was supported by the National Natural Science Foundation of China (no. 81871079 to H.G.; nos. 8173000779 and 82130043 to K.X.; nos. 81873633 and 82071276 to Y.S.); National Brain Science and Brain-like Research of China (no. 2021ZD0201704 to H.G.); National Key Research and Development Program of China (no. 2021YFA0805200 to Z.H. and J.T.); Hunan Provincial grants (nos. 2021JJ10070, 2021DK2001, 2019RS2005, and 2019SK1015 to H.G.; no. B2019138 to K.X.); Major Research Plan of the Provincial Science and Technology Foundation of Guangxi (no. AB16380214); "YUMIAOJIHUA" Project of The Maternal & Child Health Hospital of Guangxi Zhuang Autonomous Region (GXWCH-YMJH-2017005); Telethon Foundation, Telethon Undiagnosed Diseases Program (TUDP, GSP15001 to N.B.-P.); and an NIH grant (no. R01 MH101221 to E.E.E.).
Publisher Copyright:
© 2022 The Authors.
PY - 2022/8/19
Y1 - 2022/8/19
N2 - 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, G3BP2, 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 CAPRIN1, disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.
AB - 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, G3BP2, 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 CAPRIN1, disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.
UR - http://www.scopus.com/inward/record.url?scp=85135972914&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abo7112
DO - 10.1126/sciadv.abo7112
M3 - Article
C2 - 35977029
AN - SCOPUS:85135972914
VL - 8
JO - Science advances
JF - Science advances
IS - 33
M1 - eabo7112
ER -