ATRX deficiency drives aberrant type I interferon signalling through cGAS-dependent transcriptional dysregulation
Abstract The X-linked α-thalassaemia intellectual disability syndrome (ATRX) protein is a chromatin remodeller involved in transcriptional regulation and genome stability. While the importance of ATRX in development and malignancy is well recognised, its role in innate immunity is less well defined. Here we describe three unrelated patients with ATR-X syndrome carrying missense mutations in the ATPase domain of ATRX, each manifesting features of severe inflammation accompanied by persistent upregulation of interferon-stimulated gene expression in whole blood. Studies in patient-derived cells, CRISPR-engineered fibroblasts and neuronal models demonstrate that ATRX loss-of-function mutations drive enhanced type I interferon signalling through a cGAS-dependent mechanism uncoupled from the DNA sensing activity of cGAS. Mechanistically, ATRX deficiency disrupts the chromatin distribution of DAXX and H3.3, with cGAS essential for the changes in nucleosome composition and gene expression mediated by loss of ATRX. Thus, our study highlights a link between ATRX dysfunction and inflammation involving a non-canonical role of cGAS.
Authors
- Joost B. Koedijk (ORCID: https://orcid.org/0000-0001-6463-3307)
- Joseph A. Marsh (ORCID: https://orcid.org/0000-0003-4132-0628)
- Alice Lepelley (ORCID: https://orcid.org/0000-0001-8656-7291)
- Angie Fawkes (ORCID: https://orcid.org/0000-0002-0657-8319)
- Simone Pelliciari (ORCID: https://orcid.org/0000-0003-3150-9136)
- Erisa Nita
- Yanick Joseph Crow (ORCID: https://orcid.org/0000-0001-7211-7564)
- Patrick Revy (ORCID: https://orcid.org/0000-0003-0758-8022)
- Graeme R. Grimes (ORCID: https://orcid.org/0000-0002-3106-5996)
- Luís Seabra (ORCID: https://orcid.org/0000-0002-4678-3026)
- Erika Van Nieuwenhove (ORCID: https://orcid.org/0000-0002-7933-1800)
- Rebekah Tillotson (ORCID: https://orcid.org/0000-0003-2863-4569)
- Marie‐Thérèse El‐Daher (ORCID: https://orcid.org/0000-0001-7166-2763)
- Somdutta Dhir (ORCID: https://orcid.org/0000-0003-1987-3971)
- Richard C. Clark (ORCID: https://orcid.org/0000-0002-0066-1541)
- Richard J. Gibbons (ORCID: https://orcid.org/0000-0002-7680-9311)
- Mathieu Paul Rodero (ORCID: https://orcid.org/0000-0002-1300-0187)
- Gillian Rice (ORCID: https://orcid.org/0000-0002-4223-0571)
- Ge Zhu (ORCID: https://orcid.org/0000-0002-2109-4857)
- Hywel Dunn-Davies (ORCID: https://orcid.org/0000-0003-3975-788X)
- Philippe Emmanuel Gautier (ORCID: https://orcid.org/0000-0003-3019-6262)
- Tom D Deegan (ORCID: https://orcid.org/0000-0001-9639-7636)
- Evangeline Wassmer (ORCID: https://orcid.org/0000-0002-2446-1106)
- Carolina Uggenti (ORCID: https://orcid.org/0000-0003-2673-5120)
- Natalie F. Blair (ORCID: https://orcid.org/0000-0003-1720-4950)
- John H. Livingston (ORCID: https://orcid.org/0000-0002-4017-0667)
- Andreas Fellas (ORCID: https://orcid.org/0000-0002-0840-6473)
- Tom A Tait
- Bertrand Isidor (ORCID: https://orcid.org/0000-0001-6480-126X)
- Sophie Glen
- Swati Naik
- Minke HW Huibers
- Julie Vogt
- Eve L. White
Publication Details
- Journal
- Nature Communications
- Published
- 2026-10-08
- DOI
- https://doi.org/10.1038/s41467-026-78094-8
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00