Analysis of the AIRE Gene Promoter in Patients Affected by Autoimmune Polyendocrine Syndromes

Abstract

Autoimmune polyglandular syndromes (APS) are classified into four main categories, APS1-APS4. APS1 is caused by AIRE gene loss of function mutations, while the genetic background of the other APS remains to be clarified. Here, we investigated the potential association between AIRE gene promoter Single Nucleotide Polymorphisms (SNPs) and susceptibility to APS. We sequenced the AIRE gene promoter of 74 APS patients, also analyzing their clinical and autoantibody profile, and we further conducted molecular modeling studies on the identified SNPs. Overall, we found 6 SNPs (-230Y, -655R, -261M, -380S, -191M, -402S) of the AIRE promoter in patients' DNA. Interestingly, folding free energy calculations highlighted that all identified SNPs, except for -261M, modify the stability of the nucleic acid structure. A rather similar percentage of APS3 and APS4 patients had polymorphisms in the AIRE promoter. Conversely, there was no association between APS2 and AIRE promoter polymorphisms. Further AIRE promoter SNPs were found in 4 out of 5 patients with APS1 clinical diagnosis that did not harbor AIRE loss of function mutations. We hypothesize that AIRE promoter polymorphisms could contribute to APS predisposition, although this should be validated through genetic screening in larger patient cohorts and in vitro and in vivo functional studies.

Keywords: AIRE; AIRE gene promoter; autoimmune etiopathogenesis; autoimmune polyglandular syndrome; polymorphisms; sequencing.

Figure 1

Frequency of APS subtypes in the present patient’s series. Total patients with APS1: 5 (blue); total patients with APS2: 5 (orange); total patients with APS3: 47 (gray); total patients with APS4: 17 (yellow).

Figure 2

Scheme of AIRE gene and DNA secondary structure predictions. Shown is the genomic sequence scheme of AIRE showing the positions of exons/introns, the sites of the variants, and a representation of the lowest free energy DNA secondary structure (modelling was made across the nucleotide range indicated by lines). The lowest folding free energies for the wild type and the variants are displayed in the table (the arrows ↑ and ↓ flanking the variant energy values respectively indicate structural destabilization and stabilization with respect to the wild type AIRE).