Autoimmune polyglandular disease type I. Exclusion map using amplifiable multiallelic markers in a microtiter well format.

The pathogenetic background of human autoimmunity is only partially understood. By discovering the defective gene causing the autosomal recessive polyglandular autoimmune disease type I (PGD I, APECED) we hope to provide new insights into autoimmune responses in general. Here we have taken advantage of newly developed amplifiable multiallelic microsatellite markers and performed the analyses using the microtiter well format of the polymerase chain reaction. This rapid semiautomated protocol was applied to analyze 62 assigned highly polymorphic loci. The linkage analyses coupled with the EXCLUDE analysis resulted in an exclusion map of this polyglandular autoimmune disease and in the preliminary assignment of the APECED locus to chromosome 22. The method proved to be an effective and economical tool for gene mapping compared with standard blotting and hybridization.

Genetic homogeneity of autoimmune polyglandular disease type I.

Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease (MIM 240300) characterized by hypoparathyroidism, primary adrenocortical failure, and chronic mucocutaneous candidiasis. The disease is highly prevalent in two isolated populations, the Finnish population and the Iranian Jewish one. Sporadic cases have been identified in many other countries, including almost all European countries. The APECED locus has previously been assigned to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Locus heterogeneity is a highly relevant question in this disease affecting multiple tissues and with great phenotypic diversity. To solve this matter, we performed linkage and haplotype analyses on APECED families rising from different populations. Six microsatellite markers on the critical chromosomal region of 2.6 cM on 21q22.3 were analyzed. Pairwise linkage analyses revealed significant LOD scores for all these markers, maximum LOD score being 10.23. The obtained haplotype data and the geographic distribution of the great-grandparents of the Finnish APECED patients suggest the presence of one major, relatively old mutation responsible for approximately 90% of the Finnish cases. Similar evidence for one founder mutation was also found in analyses of Iranian Jewish APECED haplotypes. These haplotypes, however, differed totally from the Finnish ones. The linkage analyses in 21 non-Finnish APECED families originating from several European countries provided independent evidence for linkage to the same chromosomal region on 21q22.3 and revealed no evidence for locus heterogeneity. The haplotype analyses of APECED chromosomes suggest that in different populations APECED is due to a spectrum of mutations in a still unknown gene on chromosome 21.