Autoimmune Regulator Gene Mutation Analysis In The Patient With Autoimmune Polyendocrinopathy Syndrome Type â… 

ContextAutoimmune polyendocrinopathy syndrome type I (APS-I; OMIM 240300) is a rare autosomal recessive disorder characterized by autoimmune-mediated failure of multiple endocrine glands, associated with mutations in the autoimmune regulator (AIRE) gene. To date, about 75 different mutations have been identified throughout the entire coding region of the AIRE gene. However, the investigation of the gene has not been performed in Chinese APS-I patients.ObjectiveTo identify AIRE mutations in a Chinese family with APS-I and analyse the genotype-phenotype correlations of APS-I.MethodsTotal genomic DNA was extracted from the peripheral blood leukocytes from the proband,her parents and 50 randomly tested subjects. Polymerase chain reaction (PCR) and direct DNA sequencing were used to detect AIRE mutations. Restriction enzyme analysis was used to confirm the pathogenicity of a mutation. The genotype and phenotype of APS-I patients were gathered in order to analyse the genotype-phenotype correlations.Results1. A compound heterozygous mutations (R257X/A19T) were detected in the AIRE gene in the proband;2. A C>T transition at nucleotide 769 in exon 6 was detected in the proband, which led to introduce a premature stop codon at position 257 (R257X) and it was also detected in her mother.3. A G>A transition at nucleotide 55 in exon 1 was detected in the proband, which led to the substitution of a alanine residue with threonine (A19T) and it was also detected in her father.4. The newly identified mutation A19T was not found in PCR amplified products from 50 randomly tested subjects by restriction enzyme analysis.5. Eight single nucleotide polymorphisms (SNPS): A33A, S278R, D526D, Intron4+42 -/a, Intron9+6 g>a, Intron9+78 -/c, Intron11-28 g>c and Intron10-58 g>a were detected in the proband. Seven of them have been found in SNP database of NCBI, but Intron10-58 g>a has not been reported.6. The genotype and phenotype of 72 APS-I patients were gathered. There were 3 typical main manifestations in 6 of 7 R257X homozygous mutation patients(86%) and in 19 of 24 967～979del13bp homozygous mutation patients(80%).Conclusions1. This is the first report about AIRE mutations in Chinese APS-I kindred;2. The common Finnsh mutation R257X is reported for the first time in Asia;3. A19T mutation is novel genetic defect of APS-I, which has not been described before;4.≥80% APS-I patients have 3 typical main manifestations, who are homozygous for R257X or 967～979del13bp;5. The allelic variation in the AIRE gene cannot be the major determinant of the clinical picture of the disease. The genetic background of the individual and the environmental factors, probably play important roles in the selection of target organs for tissue destruction.