Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission

Hui Guo; Ying Li; Lu Shen; Tianyun Wang; Xiangbin Jia; Lijuan Liu; Tao Xu; Mengzhu Ou; Kendra Hoekzema; Huidan Wu; Madelyn A. Gillentine; Cenying Liu; Hailun Ni; Pengwei Peng; Rongjuan Zhao; Yu Zhang; Chanika Phornphutkul; Alexander P. A. Stegmann; Carlos E. Prada; Robert J. Hopkin; Joseph T. Shieh; Kirsty McWalter; Kristin G. Monaghan; Peter M. van Hasselt; Koen van Gassen; Ting Bai; Min Long; Lin Han; Yingting Quan; Meilin Chen; Yaowen Zhang; Kuokuo Li; Qiumeng Zhang; Jieqiong Tan; Tengfei Zhu; Yaning Liu; Nan Pang; Jing Peng; Daryl A. Scott; Seema R. Lalani; Mahshid Azamian; Grazia M. S. Mancini; Darius J. Adams; Malin Kvarnung; Anna Lindstrand; Ann Nordgren; Jonathan Pevsner; Ikeoluwa A. Osei-Owusu; Corrado Romano; Giuseppe Calabrese; Ornella Galesi; Jozef Gecz; Eric Haan; Judith Ranells; Melissa Racobaldo; Magnus Nordenskjold; Suneeta Madan-Khetarpal; Jessica Sebastian; Susie Ball; Xiaobing Zou; Jingping Zhao; Zhengmao Hu; Fan Xia; Pengfei Liu; Jill A. Rosenfeld; Bert B. A. de Vries; Raphael A. Bernier; Zhi-Qing David Xu; Honghui Li; Wei Xie; Robert B. Hufnagel; Evan E. Eichler; Kun Xia

doi:10.1126/sciadv.aax2166

Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission

Hui Guo^*, Ying Li, Lu Shen, Tianyun Wang, Xiangbin Jia, Lijuan Liu, Tao Xu, Mengzhu Ou, Kendra Hoekzema, Huidan Wu, Madelyn A. Gillentine, Cenying Liu, Hailun Ni, Pengwei Peng, Rongjuan Zhao, Yu Zhang, Chanika Phornphutkul, Alexander P. A. Stegmann, Carlos E. Prada, Robert J. HopkinJoseph T. Shieh, Kirsty McWalter, Kristin G. Monaghan, Peter M. van Hasselt, Koen van Gassen, Ting Bai, Min Long, Lin Han, Yingting Quan, Meilin Chen, Yaowen Zhang, Kuokuo Li, Qiumeng Zhang, Jieqiong Tan, Tengfei Zhu, Yaning Liu, Nan Pang, Jing Peng, Daryl A. Scott, Seema R. Lalani, Mahshid Azamian, Grazia M. S. Mancini, Darius J. Adams, Malin Kvarnung, Anna Lindstrand, Ann Nordgren, Jonathan Pevsner, Ikeoluwa A. Osei-Owusu, Corrado Romano, Giuseppe Calabrese, Ornella Galesi, Jozef Gecz, Eric Haan, Judith Ranells, Melissa Racobaldo, Magnus Nordenskjold, Suneeta Madan-Khetarpal, Jessica Sebastian, Susie Ball, Xiaobing Zou, Jingping Zhao, Zhengmao Hu, Fan Xia, Pengfei Liu, Jill A. Rosenfeld, Bert B. A. de Vries, Raphael A. Bernier, Zhi-Qing David Xu, Honghui Li, Wei Xie, Robert B. Hufnagel^*, Evan E. Eichler^*, Kun Xia^*

^*Corresponding author for this work

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

Abstract

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neuro-developmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.

Original language	English
Article number	2166
Number of pages	16
Journal	Science advances
Volume	5
Issue number	9
DOIs	https://doi.org/10.1126/sciadv.aax2166
Publication status	Published - Sept 2019

Keywords

MENTAL-RETARDATION PROTEIN
FRAGILE-X-SYNDROME
DE-NOVO MUTATION
MESSENGER-RNA
DROSOPHILA
GENES
RISK
IDENTIFICATION
ARCHITECTURE
TRANSLATION

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Cite this

Guo, H., Li, Y., Shen, L., Wang, T., Jia, X., Liu, L., Xu, T., Ou, M., Hoekzema, K., Wu, H., Gillentine, M. A., Liu, C., Ni, H., Peng, P., Zhao, R., Zhang, Y., Phornphutkul, C., Stegmann, A. P. A., Prada, C. E., ... Xia, K. (2019). Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission. Science advances, 5(9), Article 2166. https://doi.org/10.1126/sciadv.aax2166

@article{5bcd079dd3594ac8b309b015d93b45c0,

title = "Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission",

abstract = "RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neuro-developmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.",

keywords = "MENTAL-RETARDATION PROTEIN, FRAGILE-X-SYNDROME, DE-NOVO MUTATION, MESSENGER-RNA, DROSOPHILA, GENES, RISK, IDENTIFICATION, ARCHITECTURE, TRANSLATION",

author = "Hui Guo and Ying Li and Lu Shen and Tianyun Wang and Xiangbin Jia and Lijuan Liu and Tao Xu and Mengzhu Ou and Kendra Hoekzema and Huidan Wu and Gillentine, {Madelyn A.} and Cenying Liu and Hailun Ni and Pengwei Peng and Rongjuan Zhao and Yu Zhang and Chanika Phornphutkul and Stegmann, {Alexander P. A.} and Prada, {Carlos E.} and Hopkin, {Robert J.} and Shieh, {Joseph T.} and Kirsty McWalter and Monaghan, {Kristin G.} and {van Hasselt}, {Peter M.} and {van Gassen}, Koen and Ting Bai and Min Long and Lin Han and Yingting Quan and Meilin Chen and Yaowen Zhang and Kuokuo Li and Qiumeng Zhang and Jieqiong Tan and Tengfei Zhu and Yaning Liu and Nan Pang and Jing Peng and Scott, {Daryl A.} and Lalani, {Seema R.} and Mahshid Azamian and Mancini, {Grazia M. S.} and Adams, {Darius J.} and Malin Kvarnung and Anna Lindstrand and Ann Nordgren and Jonathan Pevsner and Osei-Owusu, {Ikeoluwa A.} and Corrado Romano and Giuseppe Calabrese and Ornella Galesi and Jozef Gecz and Eric Haan and Judith Ranells and Melissa Racobaldo and Magnus Nordenskjold and Suneeta Madan-Khetarpal and Jessica Sebastian and Susie Ball and Xiaobing Zou and Jingping Zhao and Zhengmao Hu and Fan Xia and Pengfei Liu and Rosenfeld, {Jill A.} and {de Vries}, {Bert B. A.} and Bernier, {Raphael A.} and Xu, {Zhi-Qing David} and Honghui Li and Wei Xie and Hufnagel, {Robert B.} and Eichler, {Evan E.} and Kun Xia",

note = "Funding Information: We are grateful to all the families who participated in this study, including participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. We are grateful to F. Gebauer for providing us the antibody to dUnr. We thank T. Brown for assistance in editing this manuscript. Funding: This work was supported by the following grants: the National Natural Science Foundation of China (NSFC) (31671114 and 81871079) to H.G., the NSFC (81330027, 81525007, and 81730036) to K.X., the Science and Technology Projects of Hunan Province (2016RS2001 and 2016JC2055) to K.X., the Simons Foundation Autism Research Initiative (SFARI 303241) and NIH (R01MH101221) to E.E.E., the NSFC (81671122) and Key R&D Program of Hunan Province (2018DK2016) to Z.H., the NSFC (91632201) and the National Basic Research Program of China (2012CB517903) to W.X., and the NIH (U54 HD079123) to J.P. This research was also supported, in part, by the Intramural Research Program of the NIH, National Eye Institute to R.B.H. and the postgraduate independent exploration project of Central South University (2014zzts063) to L.S. E.E.E. is an Publisher Copyright: Copyright {\textcopyright} 2019 The Authors.",

year = "2019",

month = sep,

doi = "10.1126/sciadv.aax2166",

language = "English",

volume = "5",

journal = "Science advances",

issn = "2375-2548",

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

number = "9",

}

Guo, H, Li, Y, Shen, L, Wang, T, Jia, X, Liu, L, Xu, T, Ou, M, Hoekzema, K, Wu, H, Gillentine, MA, Liu, C, Ni, H, Peng, P, Zhao, R, Zhang, Y, Phornphutkul, C, Stegmann, APA, Prada, CE, Hopkin, RJ, Shieh, JT, McWalter, K, Monaghan, KG, van Hasselt, PM, van Gassen, K, Bai, T, Long, M, Han, L, Quan, Y, Chen, M, Zhang, Y, Li, K, Zhang, Q, Tan, J, Zhu, T, Liu, Y, Pang, N, Peng, J, Scott, DA, Lalani, SR, Azamian, M, Mancini, GMS, Adams, DJ, Kvarnung, M, Lindstrand, A, Nordgren, A, Pevsner, J, Osei-Owusu, IA, Romano, C, Calabrese, G, Galesi, O, Gecz, J, Haan, E, Ranells, J, Racobaldo, M, Nordenskjold, M, Madan-Khetarpal, S, Sebastian, J, Ball, S, Zou, X, Zhao, J, Hu, Z, Xia, F, Liu, P, Rosenfeld, JA, de Vries, BBA, Bernier, RA, Xu, Z-QD, Li, H, Xie, W, Hufnagel, RB, Eichler, EE & Xia, K 2019, 'Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission', Science advances, vol. 5, no. 9, 2166. https://doi.org/10.1126/sciadv.aax2166

TY - JOUR

T1 - Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission

AU - Guo, Hui

AU - Li, Ying

AU - Shen, Lu

AU - Wang, Tianyun

AU - Jia, Xiangbin

AU - Liu, Lijuan

AU - Xu, Tao

AU - Ou, Mengzhu

AU - Hoekzema, Kendra

AU - Wu, Huidan

AU - Gillentine, Madelyn A.

AU - Liu, Cenying

AU - Ni, Hailun

AU - Peng, Pengwei

AU - Zhao, Rongjuan

AU - Zhang, Yu

AU - Phornphutkul, Chanika

AU - Stegmann, Alexander P. A.

AU - Prada, Carlos E.

AU - Hopkin, Robert J.

AU - Shieh, Joseph T.

AU - McWalter, Kirsty

AU - Monaghan, Kristin G.

AU - van Hasselt, Peter M.

AU - van Gassen, Koen

AU - Bai, Ting

AU - Long, Min

AU - Han, Lin

AU - Quan, Yingting

AU - Chen, Meilin

AU - Zhang, Yaowen

AU - Li, Kuokuo

AU - Zhang, Qiumeng

AU - Tan, Jieqiong

AU - Zhu, Tengfei

AU - Liu, Yaning

AU - Pang, Nan

AU - Peng, Jing

AU - Scott, Daryl A.

AU - Lalani, Seema R.

AU - Azamian, Mahshid

AU - Mancini, Grazia M. S.

AU - Adams, Darius J.

AU - Kvarnung, Malin

AU - Lindstrand, Anna

AU - Nordgren, Ann

AU - Pevsner, Jonathan

AU - Osei-Owusu, Ikeoluwa A.

AU - Romano, Corrado

AU - Calabrese, Giuseppe

AU - Galesi, Ornella

AU - Gecz, Jozef

AU - Haan, Eric

AU - Ranells, Judith

AU - Racobaldo, Melissa

AU - Nordenskjold, Magnus

AU - Madan-Khetarpal, Suneeta

AU - Sebastian, Jessica

AU - Ball, Susie

AU - Zou, Xiaobing

AU - Zhao, Jingping

AU - Hu, Zhengmao

AU - Xia, Fan

AU - Liu, Pengfei

AU - Rosenfeld, Jill A.

AU - de Vries, Bert B. A.

AU - Bernier, Raphael A.

AU - Xu, Zhi-Qing David

AU - Li, Honghui

AU - Xie, Wei

AU - Hufnagel, Robert B.

AU - Eichler, Evan E.

AU - Xia, Kun

N1 - Funding Information: We are grateful to all the families who participated in this study, including participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. We are grateful to F. Gebauer for providing us the antibody to dUnr. We thank T. Brown for assistance in editing this manuscript. Funding: This work was supported by the following grants: the National Natural Science Foundation of China (NSFC) (31671114 and 81871079) to H.G., the NSFC (81330027, 81525007, and 81730036) to K.X., the Science and Technology Projects of Hunan Province (2016RS2001 and 2016JC2055) to K.X., the Simons Foundation Autism Research Initiative (SFARI 303241) and NIH (R01MH101221) to E.E.E., the NSFC (81671122) and Key R&D Program of Hunan Province (2018DK2016) to Z.H., the NSFC (91632201) and the National Basic Research Program of China (2012CB517903) to W.X., and the NIH (U54 HD079123) to J.P. This research was also supported, in part, by the Intramural Research Program of the NIH, National Eye Institute to R.B.H. and the postgraduate independent exploration project of Central South University (2014zzts063) to L.S. E.E.E. is an Publisher Copyright: Copyright © 2019 The Authors.

PY - 2019/9

Y1 - 2019/9

N2 - RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neuro-developmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.

AB - RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neuro-developmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.

KW - MENTAL-RETARDATION PROTEIN

KW - FRAGILE-X-SYNDROME

KW - DE-NOVO MUTATION

KW - MESSENGER-RNA

KW - DROSOPHILA

KW - GENES

KW - RISK

KW - IDENTIFICATION

KW - ARCHITECTURE

KW - TRANSLATION

U2 - 10.1126/sciadv.aax2166

DO - 10.1126/sciadv.aax2166

M3 - Article

C2 - 31579823

SN - 2375-2548

VL - 5

JO - Science advances

JF - Science advances

IS - 9

M1 - 2166

ER -