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 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.

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

“…Studies in humans and animal models have revealed aberrations in dendritic spine architecture in several psychiatric disorders including depression and others related to stress (Edfawy et al, 2019;Guo et al, 2019;Yang et al, 2020). Changes in spine density and organization are thought to contribute to the behavioral disorder caused by stress exposure (Chen et al, 2020).…”

Pseudo-RNA-Binding Domains Mediate RNA Structure Specificity in Upstream of N-Ras

“…The human ortholog, Unr/CSDE1, is linked to several cellular processes, including cell migration, differentiation, and apoptosis, where it predominantly acts as a cytoplasmic RBP to regulate translation and stability of its target mRNAs ( Boussadia et al., 2003 ; Dormoy-Raclet et al., 2005 ). Attesting to its important roles in post-transcriptional regulation, Unr/CSDE1 has been linked to diseases, including Diamond-Blackfan anemia, autism, and cancer progression ( Fishbein et al., 2017 ; Guo et al., 2019 ; Horos and von Lindern, 2012 ; Sanders et al., 2012 ; Wurth et al., 2016 ; Xia et al., 2014 ).…”

Promoting axon regeneration by enhancing the non-coding function of the injury-responsive coding geneGpr151

“…First, CSDE1 is a negative regulator of neural differentiation in human stem cells because loss of CSDE1 accelerates neurogenesis (Ju Lee et al, 2017). Second, likely gene-disrupting variants in CSDE1 are associated with autism spectrum disorder (Guo et al, 2019). Interestingly, it was reported that CSDE1 knockdown promotes neurite and axon outgrowth (Guo et al, 2019).…”

“…Second, likely gene-disrupting variants in CSDE1 are associated with autism spectrum disorder (Guo et al, 2019). Interestingly, it was reported that CSDE1 knockdown promotes neurite and axon outgrowth (Guo et al, 2019). These results stimulated us to hypothesize that CSDE1 is a key target of Gpr151 mRNA for its non-coding function through non-ribosomal RBPs.…”