GENETIC HOMOGENEITY OF AUTOIMMUNE POLYGLANDULAR DISEASE TYPE-I

Autoimmune polyglandular disease type I (APECED) is an autosomal reces sive autoimmune disease (MIM 240300) characterized by hypoparathyroidi sm, primary adrenocortical failure, and chronic mucocutaneous candidia sis. The disease is highly prevalent in two isolated populations, the Finnish population and the Iranian Jewish one. Sporadic cases have bee n identified in many other countries, including almost all European co untries. The APECED locus has previously been assigned to chromosome 2 1q22.3 by linkage analyses in 14 Finnish families. Locus heterogeneity is a highly relevant question in this disease affecting multiple tiss ues and with great phenotypic diversity. To solve this matter, we perf ormed linkage and haplotype analyses on APECED families rising from di fferent populations. Six microsatellite markers on the critical chromo somal region of 2.6 cM on 21q22.3 were analyzed. Pairwise linkage anal yses revealed significant LOD scores for all these markers, maximum LO D score being 10.23. The obtained haplotype data and the geographic di stribution of the great-grandparents of the Finnish APECED patients su ggest the presence of one major, relatively old mutation responsible f or similar to 90% of the Finnish cases. Similar evidence for one found er mutation was also found in analyses of Iranian Jewish APECED haplot ypes. These haplotypes, however, differed totally from the Finnish one s. The linkage analyses in 21 non-Finnish APECED families originating from several European countries provided independent evidence for link age 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.