Abstract
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.
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References
Ahonen, P. Autoimmune polyendocrinopathy–candidosis–ectodermal dystrophy (APECED): autosomal recessive inheritance. Clin. Genet. 27, 535–542 (1985).
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).
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).
Zlotogora, J. & Shapiro, M.S. Polyglandular autoimmune syndrome type I among Iranian Jews. Med. Genet. 29, 824–826 (1992).
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).
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).
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).
Björses, P. et al Genetic homogeneity of autoimmune polyglandular disease type I. Am. J. Hum. Genet 59, 879–886 (1996).
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).
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).
Nagamine, K. Genomic organization and complete nucleotide sequence of the human PWP2 gene on chromosome 21. Genomics 42, 528–531 (1997).
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).
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).
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).
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).
Aasland, R., Gibson, T.J. & Stewart, A.F. The PHD finger: implications for chromatin-mediated transcriptional regulation. Trends Biochem. Sci. 20, 56–59 (1995).
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).
Burge, C. & Karlin, S. Prediction of complete gene structures in human genomic DNA. J. Mol. Biol. 268, 78–94 (1997).
Chen, H. et al559 potential exons of gene of human chromosome 21 by exon trapping. Genome Res. 6, 747–760 (1996).
Kozak, M. Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. Nucleic Acids Res. 12, 857–872 (1984).
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).
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).
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).
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).
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).
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).
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).
Nossal, G.J.V. Negative selection of lymphocytes. Cell 76, 229–239 (1994).
Kawasaki, K. et al. One-megabase sequence analysis of the human immunoglobulin A, gene locus. Genome Res. 7, 250–261 (1997).
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Nagamine, K., Peterson, P., Scott, H. et al. Positional cloning of the APECED gene. Nat Genet 17, 393–398 (1997). https://doi.org/10.1038/ng1297-393
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DOI: https://doi.org/10.1038/ng1297-393
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