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Genetic homogeneity of autoimmune polyglandular disease type I.

ABSTRACT: 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.

SUBMITTER: Bjorses P

PROVIDER: S-EPMC1914815 | biostudies-literature | 1996 Oct

REPOSITORIES: biostudies-literature

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Genetic homogeneity of autoimmune polyglandular disease type I.

Björses P P Aaltonen J J Vikman A A Perheentupa J J Ben-Zion G G Chiumello G G Dahl N N Heideman P P Hoorweg-Nijman J J JJ Mathivon L L Mullis P E PE Pohl M M Ritzen M M Romeo G G Shapiro M S MS Smith C S CS Solyom J J Zlotogora J J Peltonen L L

American journal of human genetics 19961001 4

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 ...[more]

PMID: 8808604

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Project description:Type 1 diabetes (T1D) and autoimmune thyroid disease (AITD) are the most frequent chronic autoimmune diseases worldwide. Several autoimmune endocrine and non-endocrine disorders tend to occur together. T1D and AITD often cluster in individuals and families, seen in the formation of autoimmune polyendocrinopathy (AP). The close relationship between these two diseases is largely explained by sharing a common genetic background. The HLA antigens DQ2 (DQA1*0501-DQB1*0201) and DQ8 (DQA1*0301-DQB1*0302), tightly linked with DR3 and DR4, are the major common genetic predisposition. Moreover, functional single nucleotide polymorphisms (or rare variants) of various genes, such as the cytotoxic T-lymphocyte- associated antigen (CTLA4), the protein tyrosine phosphatase non-receptor type 22 (PTPN22), the interleukin-2 Receptor (IL2Ra), the Vitamin D receptor (VDR), and the tumor-necrosis-factor-α (TNF) that are involved in immune regulation have been identified to confer susceptibility to both T1D and AITD. Other genes including cluster of differentiation 40 (CD40), the forkhead box P3 (FOXP3), the MHC Class I Polypeptide-Related Sequence A (MICA), insulin variable number of tandem repeats (INS-VNTR), the C-Type Lectin Domain Containing 16A (CLEC16A), the Erb-B2 Receptor Tyrosine Kinase 3 (ERBB3) gene, the interferon-induced helicase C domain-containing protein 1 (IFIH1), and various cytokine genes are also under suspicion to increase susceptibility to T1D and AITD. Further, BTB domain and CNC homolog 2 (BACH2), C-C motif chemokine receptor 5 (CCR5), SH2B adaptor protein 3 (SH2B3), and Rac family small GTPase 2 (RAC2) are found to be associated with T1D and AITD by various independent genome wide association studies and overlap in our list, indicating a strong common genetic link for T1D and AITD. As several susceptibility genes and environmental factors contribute to the disease aetiology of both T1D and AITD and/or AP subtype III variant (T1D+AITD) simultaneously, all patients with T1D should be screened for AITD, and vice versa.

Dataset Information

Genetic homogeneity of autoimmune polyglandular disease type I.

Publications

Genetic homogeneity of autoimmune polyglandular disease type I.

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