Type I interferon diseases are a heterogeneous and growing group of rare autoinflammatory monogenic diseases associated with elevated type I interferon (IFN) signaling. Previous studies have demonstrated that NCOR2 is required for the repression of the transcriptional factor IRF7, an inductor of Type I IFN, through the recruitment of the histone deacetylase 3 (HDAC3) and other transcriptional factors such as FOXO3, MYC or other proteins as the B cell lymphocyte 6 (Bcl6) to its promoters.

The patient's WES did not reveal mutations in genes described for autoimmune diseases. However, a single cell RNA analysis of the patient's peripheral blood leukocytes showed a clear interferon signature, being neutrophils and monocytes the cells expressing higher levels of Interferon Stimulated Genes (ISGs). Analysis of the Trio-WES reveals a list of possible pathogenic mutations. One of these de novo mutation encodes the transcriptional factor NCOR2 (NM_001077261: p.V1904I).

Here we demonstrate that cells from the patient express similar protein levels of NCOR2, but have higher transcript levels of IRF7, suggesting that the mutation found in NCOR2 could be affecting to the complex formation necessary to repress the expression of IRF7. Moreover, we found that the patient cells are more sensitive to the stimulation with IFN than control cells, reinforcing the theory that the feedback loop of IRF7 is damaged. Recently, we have found a second patient with the same phenotype that also presents a mutation in NCOR2 (NM_001077261: pArg1352His) which has also been included in the study. In parallel, we have used the zebrafish as a model to further characterize the phenotype by overexpressing the wild type NCOR2 and the version carrying the mutation by the injection the mRNA and analysis of the ISGs response.

Cells from patient RD1 express similar protein levels of NCOR2 compared to control, but have higher transcript levels of IRF7, suggesting that the mutation found in NCOR2 could be affecting to the complex formation necessary to repress the expression of IRF7 . The zebrafish model will also allow us to perform drug screenings to help the discovery and reposition of possible treatments to these patients.