Mutation analyses of North American APS-1 patients

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Abstract
Autoimmune polyendocrinopathy syndrome type 1 (APS‐1; MIM# 240300) is a rare autosomal recessively inherited disease characterised by destructive autoimmune diseases of endocrine glands. The gene responsible for APS‐1, known as AIRE (for autoimmune regulator), was recently identified and contains motifs suggestive of a transcription regulator. To date, nine APS‐1‐associated mutations have been identified in the AIRE gene, including two common mutations R257X and 1094‐1106del. In addition to these two mutations, we report seven novel mutations in 16 APS‐1 patients from North America. We found that 1094‐1106del and R257X were the most common mutations in this population of mixed geoethnic origin, accounting for 17/32 and 4/32 alleles, respectively. Haplotype analyses suggest that both are recurrent mutations, occurring on several different haplotypes with closely linked markers. All the novel mutations appear to be rare, occurring in only single APS‐1 families. After examining all coding sequences and exon/intron boundaries of the AIRE gene, the other APS‐1 allele remained unidentified in three patients. Genotype‐phenotype correlations for APS‐1 remain difficult, suggesting that other genetic or environmental factors, or both, influence the clinical presentation and disease progression in individual APS‐1 patients. Hum Mutat 13:69–74, 1999.