A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1

Autoimmune polyendocrinopathy type 1 (APS1) is an autosomal recessive disor der characterized by autoimmune hypoparathyroidism, autoimmune adrenocortic al failure, and mucocutaneous candidiasis. Recently, an autoimmune regulato r gene (AIRE-1), which is located on chromosome 21q22.3, has been identifie d, and mutations in European kindreds with APS1 have been described. We use d SSCP analysis and direct DNA sequencing to screen the entire 1,635-bp cod ing region of AIRE-1 in 12 British families with APS1. A 13-bp deletion (96 4del13) was found to account for 17 of the 24 possible mutant AIRE-1 allele s, in our kindreds. This mutation was found to occur de novo in one affecte d subject. A common haplotype spanning the AIRE-1 locus was found in chromo somes that carried the 964del13 mutation, suggesting a founder effect in ou r population. One of 576 normal subjects was also a heterozygous carrier of the 964del13 mutation. Six other point mutations were found in AIRE-1, inc luding two 1-bp deletions, three missense mutations (R15L, L28P, and Y90C), and a nonsense mutation (R257*). The high frequency of the 964del13 allele and the clustering of the other AIRE-1 mutations may allow rapid molecular screening for APS1 in British kindreds. Furthermore, the prevalence of the 964del13 AIRE-1 mutation may have implications in the pathogenesis of the more common autoimmune endocrinopathies in our population.