The molecular details of autoimmunity have remained to large extent uncharacterized. Using inherited diseases with a strong autoimmune component in their clinical expression as biological models could help to understand the molecular pathogenesis of abnormal immune response. One such genetic disorder is autosomal recessive polyendocrinopathy-candidiasis-ectodermal dystrophy(APECED, MIM 240300), especially enriched in the genetically isolated population of Finland. The disease is characterized by chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenocortical failure. We have assigned the APECED locus to human chromosome 21q22.3 by linkage analyses. Our linkage and haplotype analyses among non-Finnish patients worldwide demonstrated same allelic disease in all families and strongly suggested one major ancestor mutation in Finland whereas the foreign families carried a spectrum of different haplotypes.

In Finnish population linkage disequilibrium and allelic association studies were utilized to define more precisely the location of the disease gene. We restricted the critical chromosomal region for the APECED gene to a 400 kb region on 21q22.3 by ancient recombinational events observable in extended haplotypes and by linkage disequilibrium analysis. Our region of interest resigns partially within a gap in the otherwise well established physical map of chromosome 21. We have now completed a BAC-PAC-PI-cosmid contig covering the critical region for the APECED gene and verified the clone order and orientation by Fiber FISH. CpG island cloning and cDNA selection methods have been used to isolate coding sequences from the overlapping clones. Analyses of the three novel cDNAs identified on the region, the identification and cloning of APECED gene and characterization of the mutations is to be completed.

The project is funded by The Academy of Finland, the Hjelt Fund of the Foundation of Pediatric Research and Helsinki University 350 Years Anniversary Foundation.