High-resolution transcriptional impact of AIRE: effects of pathogenic variants p.Arg257Ter, p.Cys311Tyr, and polygenic risk variant p.Arg471Cys

Our cell-system approach differentiates between categories of AIRE variants on the transcriptional level, including the nonsense variant p.R257* (near complete loss of function), the p.C311Y variant associated with dominantly inherited APS-1 (severely impaired function), and the polygenic risk variant p.R471C (slightly increased function) linked to common organ-specific autoimmunity. The increased activity of p.R471C compared to wildtype indicates different molecular mechanisms for monogenic and polygenic AIRE related autoimmunity. We find that AIRE induced expression is characterised by a small absolute increase in expression levels of genes of both high and low tissue specificity.