A NOVEL POINT MUTATION IN THE AIRE GENE ASSOCIATED WITH AUTOIMMUNE POLYGLANDULAR SYNDROME TYPE 1

VITOZZI, SUSANA; CORREA, SILVIA; LOZANO, ALEJANDRO; FERNÁNDEZ, EDUARDO; QUIROGA, RODRIGO

IMMUNOGENETICS

SPRINGER

Lugar: Berlin; Año: 2023

0093-7711

The autoimmune regulator gene AIRE plays an essential role in the establishment of immune tolerance and the prevention of autoimmunity. In the thymus, AIRE is involved in the elimination of self-reactive T cells with high TCR affinity and the positive selection of regulatory Foxp3-positive cells with intermediate TCR affinity. This transcription factor plays a critical role in promoting self-tolerance in the thymus by regulating the expression of a large number of self-antigens that share the common feature of being tissue-restricted in their expression pattern in the periphery. Dysfunction of AIRE in humans causes a rare disease, autoimmune polyglandular syndrome type 1 (APS1), characterized by an autoimmune response against peripheral tissues, particularly endocrine tissues. Although a few dominant mutations have been described, the inactivation of AIRE is usually caused by recessive mutations. Recent data suggests that alterations in AIRE function contribute not only to APS1 but also to more common forms of autoimmune disease. Here we present a previously unreported missense mutation (NM_000383.2:c.260T>C) at a novel site in the AIRE gene located in exon 2, which, when inherited in conjunction with another dysfunctional AIRE allele, was associated with immune dysregulation in a pediatric patient. A comprehensive clinical analysis allowed us to confirm an APS1 diagnosis. The novel mutation detected in exon 2 of the AIRE gene in the proposita is predicted to cause a substitution from leucine to proline (p.(Leu87Pro)) in the CARD domain of the AIRE protein. To infer a possible mechanism for the phenotypic effect associated with this mutation, we performed sequence alignments, sequence conservation analysis, molecular modeling of the mutant AIRE tertiary structure and a predictive computational analysis of thermodynamic protein stability. The novel p.(Leu87Pro) mutation described here is associated with APS1, possibly by inhibiting the formation of homo-multimers.