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
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 - 2019/9/25
Y1 - 2019/9/25
N2 - 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 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.
AB - 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 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.
UR - http://www.scopus.com/inward/record.url?scp=85072635293&partnerID=8YFLogxK
U2 - 10.1126/sciadv.aax2166
DO - 10.1126/sciadv.aax2166
M3 - Article
C2 - 31579823
AN - SCOPUS:85072635293
VL - 5
JO - Science advances
JF - Science advances
IS - 9
M1 - eaax2166
ER -