Endocrine Abstracts

The autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome is an autosomal recessive disorder characterized by immune deficiency and the autoimmune destruction of endocrine organs such as the parathyroids, adrenal cortex and ovaries. APECED is caused by biallelic germline mutations of the autoimmune regulator (AIRE) gene on chromosome 21q22.3, which is expressed in thymic medullary epithelial cells and plays a key role in the development of immunological self-tolerance. We investigated 118 probands with suspected APECED for AIRE abnormalities by DNA sequence analysis, and identified biallelic mutations in 33 probands. Eighteen different AIRE mutations were detected, which comprised: eight frameshift; three splice-site; four missense; two nonsense; and one initiation codon mutation, which was predicted to alter gene transcription. The most frequent AIRE mutation was a 13 bp deletional frameshift (c.967_979del13; P.Leu323fs), which has been reported to commonly occur in the British population, and was identified in >25% of APECED probands, including in a 15 year old male, who developed hypoparathyroidism, hypoadrenalism and dental enamel hypoplasia. This proband, the son of non-consanguineous asymptomatic parents, displayed apparent homozygosity for the AIRE P.Leu323fs mutation, yet parental analysis of the AIRE gene revealed the paternal DNA to be heterozygous for the P.Leu323fs mutation, whilst this mutation was absent in the maternal DNA. To establish the mode of inheritance of the P.Leu323fs AIRE mutation, microsatellite analysis was undertaken using nine markers located across chromosome 21q21-21q22.3. This revealed that the proband was homozygous for all loci tested, and consistent with the proband having inherited two copies of the paternal mutant AIRE allele due to uniparental isodisomy. Thus, these studies demonstrate that bilallelic AIRE mutations may be caused by uniparental isodisomy rather than through an autosomal recessive mode of inheritance. Furthermore, uniparental isodisomy should be considered in APECED patients that harbour homozygous AIRE mutations, but are from non-consanguineous families.