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.

[1]  J. Perheentupa,et al.  Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. , 1990, The New England journal of medicine.

[2]  L. Peltonen,et al.  An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21 , 1994, Nature Genetics.

[3]  L. Staudt,et al.  LYSP100-associated nuclear domains (LANDs): description of a new class of subnuclear structures and their relationship to PML nuclear bodies. , 1996, Blood.

[4]  M. Renz,et al.  The major dermatomyositis-specific Mi-2 autoantigen is a presumed helicase involved in transcriptional activation. , 1995, Arthritis and rheumatism.

[5]  S. Antonarakis,et al.  Characterization of a novel gene, C21orf2, on human chromosome 21q22.3 and its exclusion as the APECED gene by mutation analysis. , 1998, Genomics.

[6]  D. Nilasena,et al.  Molecular analysis of a major antigenic region of the 240-kD protein of Mi-2 autoantigen. , 1995, The Journal of clinical investigation.

[7]  N. Shimizu,et al.  Genomic organization and complete nucleotide sequence of the TMEM1 gene on human chromosome 21q22.3. , 1997, Biochemical and biophysical research communications.

[8]  S Minoshima,et al.  One-megabase sequence analysis of the human immunoglobulin lambda gene locus. , 1997, Genome research.

[9]  N. Shimizu,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. , 1996, Biochemical and biophysical research communications.

[10]  G. J. V. Nossal,et al.  Negative selection of lymphocytes , 1994, Cell.

[11]  S. Antonarakis,et al.  Cloning of 559 potential exons of genes of human chromosome 21 by exon trapping. , 1996, Genome research.

[12]  L. Peltonen,et al.  Genetic homogeneity of autoimmune polyglandular disease type I. , 1996, American journal of human genetics.

[13]  H. Rochefort,et al.  Differential Interaction of Nuclear Receptors with the Putative Human Transcriptional Coactivator hTIF1* , 1997, The Journal of Biological Chemistry.

[14]  S. M. de la Monte,et al.  Identification and Characterization of a Leukocyte-specific Component of the Nuclear Body* , 1996, The Journal of Biological Chemistry.

[15]  J. Zlotogora,et al.  Polyglandular autoimmune syndrome type I among Iranian Jews. , 1992, Journal of medical genetics.

[16]  Cytochrome P450 1A2 is a hepatic autoantigen in autoimmune polyglandular syndrome type 1. , 1997, The Journal of clinical endocrinology and metabolism.

[17]  N. Shimizu,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. , 1997, DNA research : an international journal for rapid publication of reports on genes and genomes.

[18]  S. Antonarakis,et al.  Cloning the cDNA of human PWP2, which encodes a protein with WD repeats and maps to 21q22.3. , 1996, Genomics.

[19]  P. Ahonen.  Autoimmune polyendocrinopathy – candidosis – ectodermal dystrophy (APECED): autosomal recessive inheritance , 1985, Clinical genetics.

[20]  T. Gibson,et al.  The PHD finger: implications for chromatin-mediated transcriptional regulation. , 1995, Trends in biochemical sciences.

[21]  N. Shimizu,et al.  Genomic organization and complete nucleotide sequence of the human PWP2 gene on chromosome 21. , 1997, Genomics.

[22]  E. Uberbacher,et al.  Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[23]  S. Karlin,et al.  Prediction of complete gene structures in human genomic DNA. , 1997, Journal of molecular biology.

[24]  M. Kozak.  Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. , 1984, Nucleic acids research.

[25]  S. Antonarakis,et al.  Isolation of a human gene (HES1) with homology to an Escherichia coli and a zebrafish protein that maps to chromosome 21q22.3 , 1997, Human Genetics.

[26]  T. Tuomi,et al.  Autoantibodies against aromatic L-amino acid decarboxylase in autoimmune polyendocrine syndrome type I. , 1997, The Journal of clinical endocrinology and metabolism.

[27]  R. Uibo,et al.  Autoantibodies to cytochrome P450 enzymes P450scc, P450c17, and P450c21 in autoimmune polyglandular disease types I and II and in isolated Addison's disease. , 1994, The Journal of clinical endocrinology and metabolism.

[28]  David M. Heery,et al.  A signature motif in transcriptional co-activators mediates binding to nuclear receptors , 1997, Nature.

[29]  A. Hagemeijer,et al.  The t(10;11) translocation in acute myeloid leukemia (M5) consistently fuses the leucine zipper motif of AF10 onto the HRX gene. , 1995, Blood.