Dominant-negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes

Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disease characterized by severe and childhood onset organ-specific autoimmu-nity caused by mutations in the autoimmune regulator (AIRE) gene. More recently, dominant-negative mutations within the PHD1, PHD2, and SAND do-mains have been associated with an incompletely penetrant milder phenotype with later onset familial clustering, often masquerading as organ-specific autoim-munity. Patients with immunodeficiencies or autoimmunity where genetic ana-lyses revealed heterozygous AIRE mutations were included in the study and the dominant-negative effects of the AIRE mutations were functionally assessed in vitro. We here report additional families with phenotypes ranging from immunodeficiency, enteropathy, and vitiligo to asymptomatic carrier status. APS-1-specific autoantibodies can hint to the presence of these pathogenic AIRE variants although their absence does not rule out their presence. Our find-ings suggest functional studies of heterozygous AIRE variants and close follow-up of identified individuals and their families.

Automated summary

APS-1 is an autosomal recessive disease caused by mutations in the AIRE gene, characterized by severe and childhood onset organ-specific autoimmunity. Dominant-negative mutations in PHD1, PHD2, and SAND domains have also been associated with a milder phenotype. This study identified additional families with a range of phenotypes and emphasized the need for functional studies and close follow-up of individuals and families.