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

Autor: Corrado Romano, Magnus Nordenskjöld, Tianyun Wang, Min Long, Suneeta Madan-Khetarpal, Evan E. Eichler, Jingping Zhao, Mengzhu Ou, Wei Xie, Yu Zhang, Kirsty McWalter, Chanika Phornphutkul, Kristin G. Monaghan, Koen L.I. van Gassen, Grazia M.S. Mancini, Zhengmao Hu, Madelyn A. Gillentine, Jessica Sebastian, Ying Li, Yaowen Zhang, Jieqiong Tan, Robert J. Hopkin, Kendra Hoekzema, Jozef Gecz, Lu Shen, Meilin Chen, Zhi-Qing David Xu, Carlos E. Prada, Alexander P.A. Stegmann, Judith D. Ranells, Hailun Ni, Ting Bai, Kuokuo Li, Tengfei Zhu, Joseph T. Shieh, Robert B. Hufnagel, Darius J. Adams, Lijuan Liu, Anna Lindstrand, Daryl A. Scott, Huidan Wu, Yingting Quan, Kun Xia, Melissa Racobaldo, J Peng, Mahshid Azamian, Raphael Bernier, Rongjuan Zhao, E. Haan, Fan Xia, Pengwei Peng, Nan Pang, Malin Kvarnung, Honghui Li, Xiangbin Jia, Seema R. Lalani, Jill A. Rosenfeld, Qiumeng Zhang, Susie Ball, Lin Han, Hui Guo, Ikeoluwa A. Osei-Owusu, Giuseppe Calabrese, Ornella Galesi, Tao Xu, Xiaobing Zou, Ann Nordgren, Yaning Liu, Pengfei Liu, Cenying Liu, Jonathan Pevsner, Bert B.A. de Vries, Peter M. van Hasselt
Přispěvatelé: Clinical Genetics, MUMC+: DA KG Lab Centraal Lab (9), RS: FHML non-thematic output
Rok vydání: 2019
Předmět:
Male
Dendritic spine
Diseases and Disorders
RNA-binding protein
Synaptic Transmission
Synapse
Mice
0302 clinical medicine
Child
Non-U.S. Gov't
Research Articles
Neurons
RISK
0303 health sciences
Gene knockdown
ARCHITECTURE
Multidisciplinary
Research Support
Non-U.S. Gov't
SciAdv r-articles
RNA-Binding Proteins
MENTAL-RETARDATION PROTEIN
3. Good health
Pedigree
Fragile X syndrome
DNA-Binding Proteins
DROSOPHILA
Phenotype
Child
Preschool
Female
MESSENGER-RNA
Research Article
GENES
Neurite
Adolescent
Neurogenesis
Neurotransmission
Biology
Research Support
behavioral disciplines and activities
N.I.H
03 medical and health sciences
Young Adult
Research Support
N.I.H.
Extramural
mental disorders
medicine
Journal Article
Animals
Humans
Genetic Predisposition to Disease
FRAGILE-X-SYNDROME
Autistic Disorder
Preschool
Genetic Association Studies
030304 developmental biology
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]
IDENTIFICATION
Animal
Genetic Variation
Extramural
Human Genetics
medicine.disease
Disease Models
Animal
DE-NOVO MUTATION
Genetic Loci
Synapses
Disease Models
Autism
TRANSLATION
Neuroscience
030217 neurology & neurosurgery
Zdroj: Science advances, 5(9):eaax2166. American Association for the Advancement of Science
Science Advances, 5
Science advances, 5(9). American Association for the Advancement of Science
Science Advances
Science advances, 5(9):2166. American Association for the Advancement of Science
Science Advances, 5, 9
ISSN: 2375-2548
Popis: CSDE1 disruptive mutations are associated with autism.
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.
Databáze: OpenAIRE
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