Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission
Guo, Hui; Li, Ying; Shen, Lu; Wang, Tianyun; Jia, Xiangbin; Liu, Lijuan; Xu, Tao; Ou, Mengzhu; Hoekzema, Kendra; Wu, Huidan; Gillentine, Madelyn A.; Liu, Cenying; Ni, Hailun; Peng, Pengwei; Zhao, Rongjuan; Zhang, Yu; Phornphutkul, Chanika; Stegmann, Alexander P.A.; Prada, Carlos E.; Hopkin, Robert J.; Shieh, Joseph T.; McWalter, Kirsty; Monaghan, Kristin G.; van Hasselt, Peter M.; van Gassen, Koen; Bai, Ting; Long, Min; Han, Lin; Quan, Yingting; Chen, Meilin; Zhang, Yaowen; Li, Kuokuo; Zhang, Qiumeng; Tan, Jieqiong; Zhu, Tengfei; Liu, Yaning; Pang, Nan; Peng, Jing; Scott, Daryl A.; Lalani, Seema R.; Azamian, Mahshid; Mancini, Grazia M.S.; Adams, Darius J.; Kvarnung, Malin; Lindstrand, Anna; Nordgren, Ann; Pevsner, Jonathan; Osei-Owusu, Ikeoluwa A.; Romano, Corrado; Calabrese, Giuseppe
(2019) Science advances, volume 5, issue 9
(Article)
Abstract
RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely genedisrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients
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identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITSCLIP revealed that Csde1binding targets are enriched in autismassociated 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 autismrelated syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.
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Keywords: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN: 2375-2548
Publisher: American Association for the Advancement of Science
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 © 2019 The Authors.
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