Loss of AIRE exon 7 yields a milder phenotype supporting a dose dependent effect of AIRE in Autoimmune Polyendocrine Syndrome Type 1.

Autoimmune polyendocrine syndrome type 1 (APS-1) or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, OMIM 240300) is caused by mutations in the Autoimmune Regulator (AIRE) gene. The clinical picture is highly variable; however, most patients present severe chronic mucocutaneous candidiasis and organ-specific autoimmunity from early childhood. AIRE is crucial in negative selection of T cells and the scrutiny of different patient mutations have previously highlighted many of its molecular mechanisms. We here report patients with a mutation in the canonical donor splice site of intron 7 (c.879+1G>A), all presenting a milder adult-onset phenotype. Both the predicted altered splicing pattern including skipping of exon 7 and normal full-length AIRE mRNA were found in the patients indicating leaky rather than abolished mRNA splicing. In vitro experiments revealed that the AIRE protein lacking exon 7 has a potential to induce AIRE regulated genes and show a similar nuclear localization as wild type AIRE. Analysis of a mouse model with the corresponding splice mutation revealed reduced capacity of Aire to induce ectopic expression of tissue restricted antigens in medullary thymic epithelial cells. The occurrence of low levels of normally spliced AIRE mRNA together with an alternatively spliced AIRE mRNA leading to some residual AIRE function, seems to prevent severe disease and contribute to the observed milder phenotype, highlighting a dose-dependent effect of AIRE conferring autoimmune disease.