ABSTRACT
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/ß-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/ß-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.
Subject(s)
Autism Spectrum Disorder , DNA-Binding Proteins , Intellectual Disability , RNA-Binding Proteins , Wnt Signaling Pathway , Adolescent , Autism Spectrum Disorder/genetics , Cell Adhesion/genetics , Child , Child, Preschool , DNA-Binding Proteins/genetics , Humans , Infant , Infant, Newborn , Intellectual Disability/genetics , RNA-Binding Proteins/genetics , Young Adult , beta Catenin/geneticsSubject(s)
Bone Diseases, Developmental/genetics , Hip Dislocation, Congenital/genetics , Hip/abnormalities , Ischium/abnormalities , Patella/abnormalities , T-Box Domain Proteins/genetics , Adolescent , Adult , Bone Diseases, Developmental/complications , Bone Diseases, Developmental/epidemiology , Bone Diseases, Developmental/physiopathology , Child , Child, Preschool , Female , Hip/physiopathology , Hip Dislocation, Congenital/complications , Hip Dislocation, Congenital/epidemiology , Hip Dislocation, Congenital/physiopathology , Humans , Ischium/physiopathology , Male , Middle Aged , Mutation , Patella/physiopathology , Pedigree , Phenotype , Young AdultABSTRACT
Steroidogenic factor 1 (encoded by SF1/NR5A1) is a transcription factor with multiple target genes involved in the development and function of multiple steroidogenic and non-steroidogenic tissues. NR5A1 mutations lead to several phenotypes, including sex reversal, spermatogenesis failure, premature ovarian failure and adrenocortical insufficiency. The implication of NR5A1 mutations in spleen development anomalies was recently highlighted. We provide new evidence of this involvement, describing a novel heterozygous non-sense NR5A1 mutation in a 46,XY-DSD with polysplenia female proband and her father, who had hypospadias and asplenia.
