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Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations

GSE279078 Mus musculus (mouse) RNA-seq (gene expression) 18 samples Submitted 2025/01/06 Platform GPL24247

At a glance

RNA-seq (gene expression) · mouse · 18 samples

What it is: RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism: Mus musculus (mouse)
Samples: 18 samples: 6 conditions, mostly in triplicateGroups are read from the sample names, not from the paper. Check the list below.
Data you can get: A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper: Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutationsPLoS genetics · 2025

Summary (written by the submitters)

De novo mutations in the RNA binding protein DDX3X cause neurodevelopmental disorders including DDX3X syndrome and autism spectrum disorder. Amongst ~200 mutations identified to date, half are missense. While DDX3X loss of function is known to impair neural cell fate, how the landscape of missense mutations impacts neurodevelopment is almost entirely unknown.

Read the full summary ↓

Here, we integrate transcriptomics, proteomics, and live imaging to demonstrate clinically diverse DDX3X missense mutations perturb neural development via distinct cellular and molecular mechanisms. Using mouse primary neural progenitors, we investigate four recurrently mutated DDX3X missense variants, from clinically severe (2) to mild (2). While clinically severe mutations impair neurogenesis, mild mutations have only a modest impact on cell fate. Moreover, expression of severe mutations leads to profound neuronal death. Using a proximity labeling screen in neural progenitors, we discover DDX3X missense variants have unique protein interactors. We observe notable overlap amongst severe mutations, suggesting common mechanisms underlying altered cell fate and survival. Transcriptomic analysis and subsequent cellular investigation highlights new pathways associated with DDX3X missense variants, including upregulated DNA Damage Response. Notably, clinically severe mutations exhibit excessive DNA damage in neurons, associated with aberrant cytoplasmic DNA:RNA hybrids and formation of stress granules. These findings highlight aberrant RNA metabolism and DNA damage in DDX3X-mediated neuronal cell death. In sum our findings reveal new mechanisms by which clinically distinct DDX3X missense mutations differentially impair neurodevelopment.

Published in

Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations

Mosti F, Hoye ML, Escobar-Tomlienovich CF et al. · PLoS genetics 2025 · PMID 39836689 · doi:10.1371/journal.pgen.1011555

This dataset

Open GSE279078 in finder → Find more mouse RNA-seq datasets →

Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓

2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE279078_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓

3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1170309 and SRA study SRP537268. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 39836689) ↗

Study design

6 conditions, mostly in triplicate

No virus, ×3 WT, ×3 R326H, ×3 R376C, ×3 R488H, ×3 T532M, ×3

Supports a between-group comparison across 18 samples.

How we read this: 6 replicated groups read from 18 sample titles; they account for 18 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study

GSM8560986 No virus, rep1 No virus,
GSM8560987 No virus, rep2 No virus,
GSM8560988 No virus, rep3 No virus,
GSM8560989 WT, rep1 WT,
GSM8560990 WT, rep2 WT,
GSM8560991 WT, rep3 WT,
GSM8560992 R326H, rep1 R326H,
GSM8560993 R326H, rep2 R326H,
GSM8560994 R326H, rep3 R326H,
GSM8560995 R376C, rep1 R376C,
GSM8560996 R376C, rep2 R376C,
GSM8560997 R376C, rep3 R376C,
GSM8560998 R488H, rep1 R488H,
GSM8560999 R488H, rep2 R488H,
GSM8561000 R488H, rep3 R488H,
GSM8561001 T532M, rep1 T532M,
GSM8561002 T532M, rep2 T532M,
GSM8561003 T532M, rep3 T532M,

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