Endocrine Abstracts

The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. Mutations in AIRE cause a rare autosomal-recessive disease, autoimmune polyendocrine syndrome type 1 (APS-1). The clinical picture is highly variable, however, most patients present severe chronic mucocutaneous candidiasis and organ-specific autoimmunity from early childhood and have high levels of autoantibodies against interferon alpha and omega. Recently, it has become evident that AIRE variants also associate with more common organ-specific autoimmune diseases such as autoimmune adrenal insufficiency, gastritis, and type 1 diabetes. We have identified multiple patients with heterozygous variants in AIRE and investigated their dominant negative effect on AIRE’s gene regulation. We find that dominant negative AIRE variants cluster within the PHD1 and PHD2 domains and have a varying effect on AIRE’s transcriptional activity. As a group, these patients have fewer and milder manifestations masquerading as “common” organ-specific autoimmunity where enteropathy was the most frequent manifestation. Interestingly, a few of these patients have autoantibodies against interferon omega. By scrutiny of our national registry, we identified two female and two male APS-1 patients from three different families with late-onset APS-1 sharing a homozygous or compound heterozygous splice mutation in AIRE’s exon 7. In addition to the late onset, they also presented with a milder phenotype compared to classical APS-1. Both normal AIRE mRNA splicing and an altered splicing pattern including skipping of exon 7 were found in the patients and in the corresponding mouse model, indicating leaky rather than abolished mRNA splicing. Further, a moderately inhibited. Aire-regulated transcriptome was found in the mouse thymus. Our results underline the dose-effect of AIRE. Taken together, our results highlight the importance of functional validation of AIRE variants and suggest a dose-dependent function of AIRE.