The MouseAireGene: Comparative Genomic Sequencing, Gene Organization, and Expression

There is a wide range of human autoimmune diseases, but the molecular background of autoimmunity remains poorly understood (Ollier 1992). Despite the identification of a number of genetic susceptibility factors, the etiology of most autoimmune diseases remains elusive. In this context, the study of autoimmune conditions with Mendelian inheritance could provide a boost for unraveling pathogenic pathways involved in human autoimmunity. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy [APECED, Online Mendelian Inheritance in Man (OMIM) 240300] is an autosomal recessive disease resulting in a variable combination of failure of the parathyroid glands, adrenal cortex, gonads, and pancreatic β cells (Ahonen 1985). Ectodermal dystrophies, vitiligo, and chronic mucocutaneous candidiasis are also frequently observed among APECED patients (Ahonen et al. 1990; Perheentupa 1996). APECED is a rare disease particularly enriched in genetic isolates, such as the Finnish population, Iranian Jews, and Sardinians (Ahonen 1985; Zlotogora and Shapiro 1992; Clemente et al. 1997). After demonstration of genetic linkage and locus homogeneity on chromosome 21q22.3 (Aaltonen et al. 1994; Bjorses et al. 1996), the APECED gene was cloned and called AIRE for autoimmune regulator (The Finnish–German APECED Consortium 1997; Nagamine et al. 1997). The AIRE gene encodes a nuclear factor of unknown function that harbors two PHD zinc fingers—a modular domain found in many proteins involved in chromatin-mediated regulation of transcription (Schindler et al. 1993; Aasland et al. 1995). Moreover, striking structural similarities were observed between AIRE and human Sp100/Sp140 proteins, suggesting that they derive from a common ancestor. In addition to the zinc fingers, AIRE and Sp140 also share a putative DNA-binding domain called SAND domain and a stretch of 90 amino acids in their amino-terminal region (Gibson 1998). Sp100 proteins localize to specific nuclear structures called nuclear bodies and represent a target of autoantibodies in patients with primary biliary cirrhosis (Szostecki et al. 1990). As a first step toward investigating AIRE biochemical properties and for engineering a mouse model for APECED, we have cloned and characterized the murine AIRE homolog. Here we report comparative genomic sequence analysis of the AIRE loci and AIRE expression pattern on mouse and human histological sections.