Positional cloning of the APECED gene

Abstract

Autoimmune polyglandular syndrome type I (APS 1, also called APECED) is an autosomal-recessive disorder that maps to human chromosome 21q22.3 between markers D21S49 and D21S171 by linkage studies. We have isolated a novel gene from this region, AIRE (autoimmune regulator), which encodes a protein containing motifs suggestive of a transcription factor including two zinc-finger (PHD-finger) motifs, a proline-rich region and three LXXLL motifs. Two mutations, a C-->T substitution that changes the Arg 257 (CGA) to a stop codon (TGA) and an A-->G substitution that changes the Lys 83 (AAG) to a Glu codon (GAG), were found in this novel gene in Swiss and Finnish APECED patients. The Arg257stop (R257X) is the predominant mutation in Finnish APECED patients, accounting for 10/12 alleles studied. These results indicate that this gene is responsible for the pathogenesis of APECED. The identification of the gene defective in APECED should facilitate the genetic diagnosis and potential treatment of the disease and further enhance our general understanding of the mechanisms underlying autoimmune diseases.

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

“…Most work in the past few years on the regulation of this atypical expression process has been on the autoimmune regulator (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy) (AIRE) transcription factor, which has a major role in the expression of most self-antigens in the thymus. Homozygous loss of AIRE function in the thymus causes the debilitating autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED) syndrome in humans [19], characterised by multiple-organ autoimmune responses involving mostly endocrine glands and including high risk of type 1 diabetes [20]. In mice, targeted Aire disruption leads to a marked decrease in self-antigen expression, almost eliminating the 'promiscuous' gene expression pattern [21].…”

“…These mice, like APECED patients, have multiple autoimmune responses directed against various organs [22]. A considerable amount of work has been done on this transcription factor, demonstrating its essential role for this process and its implications for autoimmune disease [19,[21][22][23]. However, it is not known whether gene-specific regulatory mechanisms of this thymic 'promiscuous' gene expression exist.…”

Oral microbiota in autoimmune polyendocrine syndrome type 1

“…However, the clinical picture is highly variable and includes many minor disease components [2]. The Autoimmune Regulator ( AIRE) gene is the disease-causing gene [3,4]. AIRE acts as a transcriptional regulator and is almost exclusively expressed in the thymus [5] where it orchestrates the process of negative selection of self-reactive T cells and contributes to the development of regulatory T cells (Tregs) [6,7].…”

Genetic analysis of innate immunity in resistance to Candida albicans

“…14 The AIRE (autoimmune regulator) gene has been associated with the autosomal recessive syndrome autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). 15,16 This gene was identified by positional cloning after mapping to chromosome 21q by linkage analyses in 14 Finnish families 17 and subsequent confirmation in an Iranian Jewish population, giving a maximum LOD score of 10.2. 18 An additional gene effect was identified in a large consanguineous family with CMC associated with thyroid disease that segregated as an autosomal dominant trait.…”