Expansion and mechanistic insights into de novo DEAF1 variants in DEAF1-associated neurodevelopmental disorders

Abstract

De novo deleterious and heritable biallelic mutations in the DNA binding domain (DBD) of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of disorders termed DEAF1-associated neurodevelopmental disorders (DAND). RNA-sequencing using hippocampal RNA from mice with conditional deletion of Deaf1 in the central nervous system indicate that loss of Deaf1 activity results in the altered expression of genes involved in neuronal function, dendritic spine maintenance, development, and activity, with reduced dendritic spines in hippocampal regions. Since DEAF1 is not a dosage-sensitive gene, we assessed the dominant negative activity of previously identified de novo variants and a heritable recessive DEAF1 variant on selected DEAF1-regulated genes in 2 different cell models. While no altered gene expression was observed in cells over-expressing the recessive heritable variant, the gene expression profiles of cells over-expressing de novo variants resulted in similar gene expression changes as observed in CRISPR-Cas9-mediated DEAF1-deleted cells. Altered expression of DEAF1-regulated genes was rescued by exogenous expression of WT-DEAF1 but not by de novo variants in cells lacking endogenous DEAF1. De novo heterozygous variants within the DBD of DEAF1 were identified in 10 individuals with a phenotypic spectrum including autism spectrum disorder, developmental delays, sleep disturbance, high pain tolerance, and mild dysmorphic features. Functional assays demonstrate these variants alter DEAF1 transcriptional activity. Taken together, this study expands the clinical phenotypic spectrum of individuals with DAND, furthers our understanding of potential roles of DEAF1 on neuronal function, and demonstrates dominant negative activity of identified de novo variants.

Diencephalic and Neuropeptidergic Dysfunction in Zebrafish with Autism Risk Mutations

“…S16 ). Observed gene expression differences from the three lines matched published literature results for orthologs of DEAF1 , EIF4G3 , UBE2M , and RAC3 ( 6 , 52 ) ( Fig. 4A ).…”

“…Since Deaf1 is a transcription factor, some differentially expressed genes in the mutant lines are expected to be direct targets. DEAF1 is known to activate and repress its targets ( 6 , 52 ), and our mutations resulted in an approximately equal distribution of up- and down-regulated differentially-expressed genes ( Fig. 4C , fig.…”

“…As Deaf1 is a transcription factor, it is expected to produce phenotypes by directly modulating expression of its target genes. The missense mutations are predicted to impact DNA-binding or transcriptional activity but could result in more complex outcomes than truncating mutations through retained interactions with binding partners ( 6 , 52 ).…”

“…( A ) Genes shared across at least two of the four datasets. ( B ) Example expression of rac3a , one of the top downregulated genes the mouse hippocampus when Deaf1 is downregulated ( 52 ). The graph on the left compares the 23d46i, c207y, and t238p lines at 2 dpf, while the graph on the right compares the 23d46i line at 2 dpf and 6 dpf.…”

FOXO-regulated Deaf1 controls muscle regeneration through autophagy

“…One of the top candidates identified from the G-Trace screen was Deformed epidermal autoregulatory factor-1 (Deaf1). Deaf1 is an evolutionarily conserved transcription factor associated with autoimmune and neurological disorders [31, 32]. Two RNAi lines against Deaf1 significantly decreased the numbers of MuSCs (RFP+ cells) as well as differentiated cells (GFP+/RFP- cells) under normal conditions compared to control (Figure 1B-C).…”