Wnt/β-catenin pathway and cell adhesion deregulation in CSDE1-related intellectual disability and autism spectrum disorders.
E El KhouriJamal GhoumidD HayeF GiulianoL DrevillonA Briand-SuleauP De La GrangeV NauT GaillonT BienvenuH Jacquemin-SablonM GoossensS AmselemIrina GiurgeaPublished in: Molecular psychiatry (2021)
Among the genetic factors playing a key role in the etiology of intellectual disabilities (IDs) and autism spectrum disorders (ASDs), several encode RNA-binding proteins (RBPs). In this study, we deciphered the molecular and cellular bases of ID-ASD in a patient followed from birth to the age of 21, in whom we identified a de novo CSDE1 (Cold Shock Domain-containing E1) nonsense variation. CSDE1 encodes an RBP that regulates multiple cellular pathways by monitoring the translation and abundance of target transcripts. Analyses performed on the patient's primary fibroblasts showed that the identified CSDE1 variation leads to haploinsufficiency. We identified through RNA-seq assays the Wnt/β-catenin signaling and cellular adhesion as two major deregulated pathways. These results were further confirmed by functional studies involving Wnt-specific luciferase and substrate adhesion assays. Additional data support a disease model involving APC Down-Regulated-1 (APCDD1) and cadherin-2 (CDH2), two components of the Wnt/β-catenin pathway, CDH2 being also pivotal for cellular adhesion. Our study, which relies on both the deep phenotyping and long-term follow-up of a patient with CSDE1 haploinsufficiency and on ex vivo studies, sheds new light on the CSDE1-dependent deregulated pathways in ID-ASD.
Keyphrases
- autism spectrum disorder
- intellectual disability
- cell adhesion
- rna seq
- stem cells
- cell proliferation
- case report
- high throughput
- attention deficit hyperactivity disorder
- single cell
- biofilm formation
- genome wide
- staphylococcus aureus
- pseudomonas aeruginosa
- cell migration
- dna methylation
- wastewater treatment
- candida albicans
- big data
- structural basis