Nature Genetics
17, 393 - 398 (1997)
doi:10.1038/ng1297-393
Positional cloning of the APECED geneKentaro Nagamine1, 2, *, Pärt Peterson3, *, Hamish S. Scott4, *, Jun Kudoh1, Shinsei Minoshima1, Maarit Heino3, Kai J. E. Krohn3, Maria D. Lalioti4, Primus E. Mullis5, Stylianos E. Antonarakis4, Kazuhiko Kawasaki1, Shuichi Asakawa1, Fumiaki Ito2
& Nobuyoshi Shimizu1, 6
1Department of Molecular Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan.
2Department of Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka 573-01, Japan.
3Institute of Medical Technology and University Hospital, University of Tampere, 33101 Tampere, Finland.
4 laboratory of Human Molecular Genetics, Department of Genetics and Microbiology, University of Geneva Medical School and
4Division of Medical Genetics, Cantonal Hospital of Geneva, 1211 Geneva 4, Switzerland.
5Department of Paediatrics, University of Bern, Bern, Switzerland.
*K.N., P.P. and H.S.S. contributed equally to this work.
6e-mail: shimizu@dmb.med.keio.ac.jp 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 AG 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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