De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders
Year: 2022
Type: article
Study design: Observational Study
Abstract: 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.
Source: Science Advances
Authors: Xiangbin Jia, Shujie Zhang, Senwei Tan, Bing Du, Mei He, Haisong Qin, Jia Chen, Xinyu Duan, Jingsi Luo, Fei Chen, Luping Ouyang, Jian Wang, Guodong Chen, Bin Yu, Ge Zhang, Zimin Zhang, Yongqing Lyu, Yi Huang, Jian Jiao, Jin Yun (Helen) Chen, Kathryn J. Swoboda, Emanuele Agolini, Antonio Novelli, Chiara Leoni, Giuseppe Zampino, Gerarda Cappuccio, Nicola Brunetti-Pierri, Benedicte Gerard, Emmanuelle Ginglinger, Julie Richer, Hugh McMillan, Alexandre White-Brown, Kendra Hoekzema, Raphael A. Bernier, Evangeline C. Kurtz-Nelson, Rachel K. Earl, Claartje Meddens, Marielle Alders, Meredith Fuchs, Roseline Caumes, Perrine Brunelle, Thomas Smol, Ryan Kuehl, Debra-Lynn Day-Salvatore, Kristin G. Monaghan, Michelle M. Morrow, Evan E. Eichler, Zhengmao Hu, Ling Yuan, Jieqiong Tan, Kun Xia, Yiping Shen, Hui Guo
Institutions: Central South University, Shanghai Jiao Tong University, Shanghai Children's Medical Center, Guangxi Maternal and Child Health Hospital, Hunan Provincial Maternal and Child Health Hospital, Massachusetts General Hospital, Mass General Brigham, Army Medical University, Daping Hospital, West China Hospital of Sichuan University, Harvard University, Bambino Gesù Children's Hospital, Agostino Gemelli University Polyclinic, Università Cattolica del Sacro Cuore, Federico II University Hospital, Telethon Institute Of Genetics And Medicine, University of Naples Federico II, Hôpitaux Universitaires de Strasbourg, Centre Hospitalier de Mulhouse, Children's Hospital of Eastern Ontario, Montreal Children's Hospital, McGill University, University of Ottawa, University of Washington, Indiana University School of Medicine, University Medical Center Utrecht, Amsterdam University Medical Centers, University of Amsterdam, Pediatrics and Genetics, Centre Hospitalier Universitaire de Lille, Université de Lille, Maladies RAres du DEveloppement embryonnaire et du MEtabolisme, Saint Peter's University Hospital, Howard Hughes Medical Institute, Chinese Academy of Sciences, Center for Excellence in Brain Science and Intelligence Technology, University of South China, Boston Children's Hospital
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
OpenAlex ID: W4292264352