26 jan. 2026
El-Daher et al., (BioRxiv), DOI: 10.1101/2025.11.19.685761
Keywords:
Interferon
Autoinflammation
Epigenetics
Main Findings:
X-linked alpha thalassaemia intellectual disability (ATR-X) syndrome is an X-linked recessive disorder caused by mutations in the ATRX gene. It is characterized by intellectual disability, distinctive facial features, genital anomalies, and alpha-thalassemia. ATRX encodes a chromatin remodeler involved in transcriptional regulation and genomic stability, with established roles in development and cancer. However, the function of ATRX in innate immunity remains poorly understood.
A recent preprint by El-Daher et al. describes two unrelated ATR-X patients who share a Y1758C substitution in the ATRX gene. In addition to expected phenotypes, both patients exhibited intracranial calcifications and persistent upregulation of interferon-stimulated genes (ISGs) in whole blood. These features have not previously been described in ATR-X syndrome, but are hallmarks of a class of autoinflammatory disorders referred to as Type I Interferonopathies.
The authors report elevated IFN-β expression and interferon scores (based on seven ISGs) in patient blood across multiple draws, as well as in patient-derived primary fibroblasts, ATRX knockout and Y1758C knock-in immortalized fibroblasts, Y1758C knock-in iPSCs, and iPSC-derived forebrain neurons. Treatment with anifrolumab, an IFNAR1 antagonist, reduced expression of 35 out of 183 upregulated ISGs, suggesting incomplete dependence on canonical interferon receptor signaling.
Strikingly, cGAS knockout fully rescued IFN-β expression, interferon scores, and pSTAT1 levels. cGAS is a cytosolic double-stranded DNA sensor that catalyzes the production of cGAMP, triggering STING-dependent induction of type I interferons. Dysregulated activation of this pathway underlies several Interferonopathies, including Aicardi-Goutières syndrome (AGS). Although classically viewed as a cytosolic protein, cGAS has recently been shown to localize to the nucleus, suggesting additional non-canonical functions.
While interferon induction in ATRX deficient cells is cGAS-dependent, the authors show that this does not involve the canonical DNA sensing pathway. ATRX mutant cells showed no increase in cGAMP levels and no changes in phosphorylation of STING, TBK1, NF-κB, or IRF3. Furthermore, neither STING knockout nor expression of a catalytically inactive cGAS mutant rescued the interferon signature, indicating that cGAS enzymatic activity is dispensable.
To investigate the epigenetic activities of ATRX, the authors used CUT&Tag and salt-elution fractionation.While the Y1758C mutation did not alter ATRX-chromatin binding, it did alter the transcription of ATRX-bound genes. The authors conclude that loss of ATRX function affects the chromatin landscape, leading to the altered distributions of the histone chaperone DAXX and histone variant H3.3, and associated changes in gene transcription. In this context, nuclear cGAS regulates ATRX-mediated chromatin remodelling.
This study identifies ATRXY1758C as a novel interferonopathy-associated mutation and reveals an unexpected transcriptional role for cGAS, independent of its catalytic activity. Future studies should investigate the specific mechanisms by which cGAS modulates the chromatin landscape in ATRX deficiency and other autoinflammatory contexts.
Limitations:
Additional studies would be valuable to further clarify the mechanisms by which cGAS regulates the interaction between ATRX and DAXX, as well as to explore other contexts in which cGAS exerts transcriptional control. The manuscript could also benefit from a more detailed discussion of how these findings might translate to clinical practice for ATR-X patients. While the authors report a modest in vitro response to anifrolumab, it would be informative to know whether either patient was subsequently treated with anifrolumab, a JAK inhibitor, or a cGAS inhibitor (while there are no FDA-approved cGAS inhibitors, Ventus Therapeutics' VENT-03 is a current small-molecule candidate in Phase 2 trials), and whether such treatment was associated with changes in clinical outcomes.
Significance/Novelty:
This study characterizes a previously unrecognized type I interferonopathy caused by a loss-of-function mutation in the chromatin remodeler ATRX. In addition, it uncovers a non-canonical role for cGAS in driving interferon signaling independently of its classical pathway. These findings reveal a new conceptual framework in which cGAS governs type I interferon responses not only through cytosolic DNA sensing, but also through direct transcriptional regulation.
Credit: Reviewed by Rachel Geltman as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.
The author declares no conflict of interests in relation to their involvement in the review.