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

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

doi:https://doi.org/10.1126/sciadv.abo7112

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

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 ChenKathryn 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

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	eabo7112
Pages (from-to)	eabo7112
Journal	Science advances
Volume	8
Issue number	33
DOIs	https://doi.org/10.1126/sciadv.abo7112
Publication status	Published - 19 Aug 2022

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Jia, X., Zhang, S., Tan, S., du, B., He, M., Qin, H., Chen, J., Duan, X., Luo, J., Chen, F., Ouyang, L., Wang, J., Chen, G., Yu, B., Zhang, G., Zhang, Z., Lyu, Y., Huang, Y., Jiao, J., ... Guo, H. (2022). De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders. Science advances, 8(33), eabo7112. Article eabo7112. https://doi.org/10.1126/sciadv.abo7112

@article{e396027133fa4046aa808a46e6af612c,

title = "De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders",

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.",

author = "Xiangbin Jia and Shujie Zhang and Senwei Tan and Bing du and Mei He and Haisong Qin and Jia Chen and Xinyu Duan and Jingsi Luo and Fei Chen and Luping Ouyang and Jian Wang and Guodong Chen and Bin Yu and Ge Zhang and Zimin Zhang and Yongqing Lyu and Yi Huang and Jian Jiao and Chen, {Jin Yun Helen} and Swoboda, {Kathryn J.} and Emanuele Agolini and Antonio Novelli and Chiara Leoni and Giuseppe Zampino and Gerarda Cappuccio and Nicola Brunetti-Pierri and Benedicte Gerard and Emmanuelle Ginglinger and Julie Richer and Hugh McMillan and Alexandre White-Brown and Kendra Hoekzema and Bernier, {Raphael A.} and Kurtz-Nelson, {Evangeline C.} and Earl, {Rachel K.} and Claartje Meddens and Marielle Alders and Meredith Fuchs and Roseline Caumes and Perrine Brunelle and Thomas Smol and Ryan Kuehl and Debra-Lynn Day-Salvatore and Monaghan, {Kristin G.} and Morrow, {Michelle M.} and Eichler, {Evan E.} and Zhengmao Hu and Ling Yuan and Jieqiong Tan and Kun Xia and Yiping Shen and Hui Guo",

note = "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: {\textcopyright} 2022 The Authors.",

year = "2022",

month = aug,

day = "19",

doi = "https://doi.org/10.1126/sciadv.abo7112",

language = "English",

volume = "8",

pages = "eabo7112",

journal = "Science advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "33",

}

Jia, X, Zhang, S, Tan, S, du, B, He, M, Qin, H, Chen, J, Duan, X, Luo, J, Chen, F, Ouyang, L, Wang, J, Chen, G, Yu, B, Zhang, G, Zhang, Z, Lyu, Y, Huang, Y, Jiao, J, Chen, JYH, Swoboda, KJ, Agolini, E, Novelli, A, Leoni, C, Zampino, G, Cappuccio, G, Brunetti-Pierri, N, Gerard, B, Ginglinger, E, Richer, J, McMillan, H, White-Brown, A, Hoekzema, K, Bernier, RA, Kurtz-Nelson, EC, Earl, RK, Meddens, C, Alders, M, Fuchs, M, Caumes, R, Brunelle, P, Smol, T, Kuehl, R, Day-Salvatore, D-L, Monaghan, KG, Morrow, MM, Eichler, EE, Hu, Z, Yuan, L, Tan, J, Xia, K, Shen, Y & Guo, H 2022, 'De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders', Science advances, vol. 8, no. 33, eabo7112, pp. eabo7112. https://doi.org/10.1126/sciadv.abo7112

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

AU - Xia, Kun

AU - Shen, Yiping

AU - Guo, Hui

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 - https://doi.org/10.1126/sciadv.abo7112

DO - https://doi.org/10.1126/sciadv.abo7112

M3 - Article

C2 - 35977029

SN - 2375-2548

VL - 8

SP - eabo7112

JO - Science advances

JF - Science advances

IS - 33

M1 - eabo7112

ER -

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

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