POSITIONAL CLONING OF THE APECED GENE

Autoimmune polyglandular syndrome type I (APS 1, also called APECED) i s an autosomal-recessive disorder that maps to human chromosome 21q22. 3 between markers D21S49 and D21S171 by linkage studies. We have isola ted a novel gene from this region, AIRE (autoimmune regulator), which encodes a protein containing motifs suggestive of a transcription fact or including two zinc-finger (PHD-finger) motifs, a proline-rich regio n and three LXXLL motifs. Two mutations, a C-->T substitution that cha nges 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 thi s novel gene in Swiss and Finnish APECED patients. The Arg257stop (R25 7X) is the predominant mutation in Finnish APECED patients, accounting for 10/12 alleles studied. These results indicate that this gene is r esponsible for the pathogenesis of APECED. The identification of the g ene defective in APECED should facilitate the genetic diagnosis and po tential treatment of the disease and further enhance our general under standing of the mechanisms underlying autoimmune diseases.