Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission
Hui Guo,Hui Guo,Ying Li,Lu Shen,Tianyun Wang,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 L.I. 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,J Peng,Daryl A. Scott,Seema R. Lalani,Mahshid Azamian,Grazia M.S. Mancini,Darius J. Adams,Malin Kvarnung,Malin Kvarnung,Anna Lindstrand,Anna Lindstrand,Ann Nordgren,Ann Nordgren,Jonathan Pevsner,Jonathan Pevsner,Ikeoluwa A. Osei-Owusu,Ikeoluwa A. Osei-Owusu,Corrado Romano,Giuseppe Calabrese,Ornella Galesi,Jozef Gecz,E. Haan,Judith D. Ranells,Melissa Racobaldo,Magnus Nordenskjöld,Magnus Nordenskjöld,Suneeta Madan-Khetarpal,Jessica Sebastian,Susie Ball,Xiaobing Zou,Jingping Zhao,Zhengmao Hu,Fan Xia,Fan Xia,Pengfei Liu,Pengfei Liu,Jill A. Rosenfeld,Bert B.A. de Vries,Raphael Bernier,Zhi-Qing David Xu,Honghui Li,Wei Xie,Robert B. Hufnagel,Evan E. Eichler,Kun Xia +82 more
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TLDR
A new autism-related syndrome is defined and the functional role of CSDE1 in synapse development and synaptic transmission is highlighted, which is linked to overgrowth of neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission.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 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.read more
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