Novel mutations of the autoimmune regulator gene in two siblings with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is the first multiple autoimmune disease that has been shown to be caused by m utations of a single gene named autoimmune regulator (AIRE). Fourteen diffe rent mutations of the AIRE gene have been identified in 61 patients from 55 families with APECED. However there has been no report documenting AIRE ge ne mutations in the Asian population. We report on 2 siblings with variable manifestations of APECED who were bor n to a Japanese mother and a Korean father. The 11-yr-old girl had intracta ble thrush and ungual candidiasis, hypoparathyroidism, and occipital alopec ia. The 9-yr-old boy had mild ungual candidiasis alone. Direct sequencing r evealed novel frameshift mutations of the AIRE gene: an insertion of a cyto sine at nucleotide 29635 at the exon 10 (29635insC), which should lead to a premature termination at the codon 371, producing a truncated protein miss ing the second plant homeodomain-type zinc finger motif and the third LXXLL motif, and a deletion of a guanine at nucleotide 33031 at the exon 13 (330 31delG), which should result in a premature termination at the codon 520, y ielding a truncated protein missing the third LXXLL motif. The mother was h eterozygous for 29635insC, and the father was heterozygous for 33031delG. T he frameshift mutations were undetected in 40 alleles of 20 Japanese contro l subjects. The results imply that the C-terminus of AIRE protein including the third LXXLL motif plays a critical role in the development of APECED, and that the phenotypic spectrum can vary between siblings with the same mu tations.