Genetics of autoimmune hypoparathyroidism Mini - review

Primary hypoparathyroidism not only occurs as an isolated idiopathic autoimmune disease (idiopathic hypoparathyroidism) but also as a component disease within the scope of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Hypoparathyroidism constitutes the major endocrine component disease in APECED occurring in 80-90% of patients and manifests during childhood. The inheritance of APECED, monogenic and autosomal-recessive, is due to a defect in a single gene, called autoimmune regulator gene (AIRE) which has been identified in 1997 and mapped to chromosome 21. So far, 45 different mutations have been detected throughout the entire coding region of the AIRE gene. Two mutations in exon 6 (R257X) and exon 8 (13-bp deletion), occur most frequently in European and North American populations, respectively. They are responsible for the expression of a truncated autoimmune regulator protein. There is evidence that the AIRE protein has a central role in maintenance of immune tolerance. It has multiple domains which are discussed to be involved in transcriptional activity, nuclear transport, DNA binding, and homomultimerization. Mutational analysis of AIRE gene allows to identify patients at risk for APECED. On the other hand, it can help to distinguish patients with APECED from those with isolated hypoparathyroidism, and thereby, avoiding family members not having APECED of unnecessary follow-up. However, the absence of a mutation in the AIRE gene does not exclude the APECED. Therefore, diagnosis is dependent on the determination of the clinical picture of the syndrome.