Endocrine Abstracts (2002) 3 P157

Compound heterozygous AIRE-1 mutations in autoimmune polyendocrinopathy type 1

MR Bowl, JJO Turner, MA Nesbit, B Harding & RV Thakker

Molecular Endocrinology Group, Nuffield Department of Clinical Medicine, University of Oxford, OX3 9DU, UK.

Autoimmune polyendocrinopathy type 1 (APS1) is an autosomal recessive disorder characterised by hypoparathyroidism, adrenocortical failure, and mucocutaneous candidiasis. The gene causing APS1 is the autoimmune regulator (AIRE-1) gene, which maps to 21q22.3 and consists of 14 exons. The AIRE-1 protein, comprising of 545 amino acids, contains two PHD zinc-finger motifs, a proline rich region and four LXXLL motifs, consistent with its role as a transcription factor. Over 25 different AIRE-1 mutations have been reported with the majority predicting a truncated protein product that results in loss or disruption of at least one PHD zinc finger motif. Two such mutations, accounting for more than 85% of APS1 disease alleles, are a nonsense mutation, Arg257Stop, that occurs in >80% of Finnish patients, and a 13bp deletion (1094-1106del) that occurs in >70% of British patients. We have investigated a 7 year old boy with APS1 for AIRE-1 mutations. The patient presented at 3.5 years of age with carpo-pedal spasms and investigations revealed hypocalcaemia with an undetectable circulating PTH concentration. In addition to the hypoparathyroidism, he also developed moniliasis and alopecia totalis. Adrenocortical and thyroid functions were normal. Treatment with alphacalcidol restored normocalcaemia. Utilising patient leukocyte DNA, PCR amplification and sequencing of the 14 AIRE-1 exons revealed the presence of two mutations, which consisted of a maternally inherited Arg257Stop mutation and a paternally inherited 13bp deletion (1094-1106del). The nonsense mutation predicts a truncated protein of 256 amino acids, and the 13bp deletion predicts a frameshift with 50 missense amino acids followed by a premature termination signal at codon 372. These predict a loss of at least one PHD zinc finger motif. Thus, the patient is a compound heterozygote for inactivating AIRE-1 mutations, whilst the parents, who are phenotypically normal, are heterozygous carriers. These findings are consistent with the autosomal recessive inheritance of APS1.

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