Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Positional cloning of the APECED gene


Autoimmune polyglandular syndrome type I (APS 1, also called APECED) is an autosomal-recessive disorder that maps to human chromosome 21q22.3 between markers D21S49 and D21S171 by linkage studies. We have isolated a novel gene from this region, AIRE (autoimmune regulator), which encodes a protein containing motifs suggestive of a transcription factor including two zinc-finger (PHD-finger) motifs, a proline-rich region and three LXXLL motifs. Two mutations, a C→T substitution that changes the Arg 257 (CGA) to a stop codon (TGA) and an A→G substitution that changes the Lys 83 (AAG) to a Glu codon (GAG), were found in this novel gene in Swiss and Finnish APECED patients. The Arg257stop (R257X) is the predominant mutation in Finnish APECED patients, accounting for 10/12 alleles studied. These results indicate that this gene is responsible for the pathogenesis of APECED. The identification of the gene defective in APECED should facilitate the genetic diagnosis and potential treatment of the disease and further enhance our general understanding of the mechanisms underlying autoimmune diseases.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. Ahonen, P. Autoimmune polyendocrinopathy–candidosis–ectodermal dystrophy (APECED): autosomal recessive inheritance. Clin. Genet. 27, 535–542 (1985).

    CAS  Article  Google Scholar 

  2. Ahonen, P., Myllarniemi, S., Sipila, I. & Perheentupa, J. Clinical variation of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) in a series of 68 patients. N. Engl. J. Med. 322, 1829–1836 (1990).

    CAS  Article  Google Scholar 

  3. Aaltonen, J., Bjorses, P.L, Perheentupa, J. & Peltonen, L An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nature Genet. 8, 83–87 (1994).

    CAS  Article  Google Scholar 

  4. Zlotogora, J. & Shapiro, M.S. Polyglandular autoimmune syndrome type I among Iranian Jews. Med. Genet. 29, 824–826 (1992).

    CAS  Article  Google Scholar 

  5. Uibo, R. et al 450 enzymes P450scc, P450c17 and P450c21 in autoimmune polyglandular disease types I and II and in isolated Addison's disease. J. Clin. Endocrinol. Metab. 78, 323–328 (1994).

    CAS  PubMed  Google Scholar 

  6. Husebye, E.S. et al. Autoantibodies against aromatic L–amino acid decarboxylase in autoimmune polyendocrine syndrome type I. J. Clin. Endocrinol. Metab. 147–150 (1997).

    CAS  Google Scholar 

  7. Clemente, M.G. et al. Cytochrome P450 1A2 is a hepatic autoantigen in autoimmune polyglandular syndrome type 1. J. Clin. Endocrinol. Metab. 82, 1353–1361 (1997).

    CAS  PubMed  Google Scholar 

  8. Björses, P. et al Genetic homogeneity of autoimmune polyglandular disease type I. Am. J. Hum. Genet 59, 879–886 (1996).

    PubMed  PubMed Central  Google Scholar 

  9. Kudoh, J. et al. Localization of 16 exons to a 450-kb region involved in the autoimmune polyglandular disease type I (APECED) on human chromosome 21q22.3. DNA Res. 4, 45–52 (1997).

    CAS  Article  Google Scholar 

  10. Nagamine, K. et al. Isolation of cDNA for a novel human protein KNP-I that is homologous to the E. coli SCRP-27A protein from the autoimmune polyglandular disease type I (APECED) region of chromosome 21q22.3. Biochem. Biophys. Res. Commun. 225, 608–616 (1996).

    CAS  Article  Google Scholar 

  11. Nagamine, K. Genomic organization and complete nucleotide sequence of the human PWP2 gene on chromosome 21. Genomics 42, 528–531 (1997).

    CAS  Article  Google Scholar 

  12. Nagamine, K. et al. Genomic organization and complete nucleotide sequence of the TMEM1 gene on human chromosome 21q22.3. Biochem. Biophys. Res. Commun. 235, 185–190 (1997).

    CAS  Article  Google Scholar 

  13. Lalioti, M.D. et al. Cloning the cDNA of human PWP2, which encodes a protein with WD repeats and maps to 21q22.3. Genomics 35, 321–327 (1996).

    CAS  Article  Google Scholar 

  14. Scott, M.S., Chen H., C, Lalioti, M.D .& Antonarakis, S.E. Isolation of a human gene (HES1) with homology to an Escherichia coli and a zebrafish protein which maps to chromsome 21q22.3. Hum. Genet. 99, 616–623 (1997).

    CAS  Article  Google Scholar 

  15. Scott, H.S. et al. Characterization of a novel gene, C21orf2, in human chromosome 21q22.3, and its exclusion as the APECED gene by mutation analysis. Genomics (in the press).

  16. Aasland, R., Gibson, T.J. & Stewart, A.F. The PHD finger: implications for chromatin-mediated transcriptional regulation. Trends Biochem. Sci. 20, 56–59 (1995).

    CAS  Article  Google Scholar 

  17. Uberbacher, E.C. & Mural, R.J. Locating protein-coding regions inhuman DNA sequences by a multiple sensor-neural network approach. Proc.Natl. Acad. Sci. USA 88, 11261–11265 (1991).

    CAS  Article  Google Scholar 

  18. Burge, C. & Karlin, S. Prediction of complete gene structures in human genomic DNA. J. Mol. Biol. 268, 78–94 (1997).

    CAS  Article  Google Scholar 

  19. Chen, H. et al559 potential exons of gene of human chromosome 21 by exon trapping. Genome Res. 6, 747–760 (1996).

    CAS  Article  Google Scholar 

  20. Kozak, M. Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. Nucleic Acids Res. 12, 857–872 (1984).

    CAS  Article  Google Scholar 

  21. Heery, D.M., Kalkhoven, E., Hoare, S. & Parker, N.G. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387, 733–736 (1997).

    CAS  Article  Google Scholar 

  22. Seeig, H.P. et al. The major dermatomyositis-specific Mi-2 autoantigen is a presumed helicase involved in transcriptional activation. Arthritis Rheum. 38, 1389–1399 (1995).

    Article  Google Scholar 

  23. Ge, Q., Nilasena, D.S., O‘Brien, C.A., Frank, M.B., Targoff, I.N. Molecular analysis of a major antigenic region of the 240-kD protein of Mi-2 autoantigen. J. Clin. Invest. 96, 1730–1737 (1995).

    CAS  Article  Google Scholar 

  24. Thenot, S., Henriquet, C., Rochefort, H. & Cavailles, V. Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1. J. Biol. Chem. 272, 12062–12068 (1997).

    CAS  Article  Google Scholar 

  25. Bloch, D.B., de la Monte, S.M., Guigaouri, P., Filippov, A. & Bloch, K.D. Identification and characterization of a leukocyte-specific component of the nuclear body. J. Biol. Chem. 271, 29198–29204 (1996).

    CAS  Article  Google Scholar 

  26. Dent, A.L. et al. LYSPIOO-associated nuclear domains (LANDs): description of a new class of subnuclear structures and their relationship to PML nuclear bodies. Blood 88, 1423–1426 (1996).

    CAS  PubMed  Google Scholar 

  27. Chaplin, T. et al. The t(10;11) translocation in acute myeloid leukemia (M5) consistently fuses the leucine zipper motif of AF10 onto the HRX gene. Blood 86, 2073–2076 (1995).

    CAS  PubMed  Google Scholar 

  28. Nossal, G.J.V. Negative selection of lymphocytes. Cell 76, 229–239 (1994).

    CAS  Article  Google Scholar 

  29. Kawasaki, K. et al. One-megabase sequence analysis of the human immunoglobulin A, gene locus. Genome Res. 7, 250–261 (1997).

    CAS  Article  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Nobuyoshi Shimizu.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nagamine, K., Peterson, P., Scott, H. et al. Positional cloning of the APECED gene. Nat Genet 17, 393–398 (1997).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing