Biology subjects

Rodero, M. P.

Publications and source records attributed to Rodero, M. P..

3 recordsLinked to original sources

bioRxiv2025

ATRX Deficiency Drives Aberrant Type I Interferon Signalling Through cGAS-Dependent Transcriptional Dysregulation

The X-linked -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. In two unrelated patients demonstrating cerebral white matter disease, learning difficulties and a persistent upregulation of interferon stimulated gene expression in whole blood, we identified the same Y1758C missense substitution in ATRX. Using patient-derived cells, engineered fibroblasts and neuronal models, we show that this substitution, and other loss of function mutations in ATRX, result in enhanced type I interferon signalling through a cGAS-dependent mechanism uncoupled from the DNA sensing activity of cGAS. Loss of ATRX function leads to alterations in the chromatin distribution of DAXX and H3.3, with cGAS essential for the changes in nucleosome composition and gene expression mediated by ATRX deficiency. Thus, our study highlights a previously unrecognized link between ATRX dysfunction and inflammation involving a non-canonical role of cGAS.

immunology↗

bioRxiv2021

Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype, and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A, and recorded up-regulated ISG expression and interferon alpha protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy. SummaryDominant-negative mutations in ATAD3A, a ubiquitously expressed mitochondrial protein, cause mitochondrial DNA-dependent up-regulation of type I interferon signaling in the context of neurological disease and autoimmunity, thereby defining a novel type I interferonopathy.

immunology↗

bioRxiv2021

Differential levels of IFNα subtypes in autoimmunity and viral infection

Type I interferons are essential for host response to viral infections, while dysregulation of their response can result in autoinflammation or autoimmunity. Among IFN (alpha) responses, 13 subtypes exist that signal through the same receptor, but have been reported to have different effector functions. However, the lack of available tools for discriminating these closely related subtypes, in particular at the protein level, has restricted the study of their differential roles in disease. We developed a digital ELISA with specificity and high sensitivity for the IFN2 subtype. Application of this assay, in parallel with our previously described pan-IFN assay, allowed us to study different IFN protein responses following cellular stimulation and in diverse patient cohorts. We observed different ratios of IFN protein responses between viral infection and autoimmune patients. This analysis also revealed a small percentage of autoimmune patients with high IFN2 protein measurements but low pan-IFN measurements. Correlation with an ISG score and functional activity showed that in this small sub group of patients, IFN2 protein measurements did not reflect its biological activity. This unusual phenotype was partly explained by the presence of anti-IFN auto-antibodies in a subset of autoimmune patients. This study reports ultrasensitive assays for the study of IFN proteins in patient samples and highlights the insights that can be obtained from the use of multiple phenotypic readouts in translational and clinical studies.

immunology↗