Mutational analysis of the PTH 3′‐untranslated region in parathyroid disorders

Abstract

Sequence alterations in untranslated regions (UTRs) of genes are important contributors to human diseases, including hereditary thrombophilia, hereditary hyperferritinaemia-cataract and fragile X mental retardation syndromes. Recently, functional studies of the 3'-UTR of the PTH gene, encoding parathyroid hormone, have highlighted it as a potential target for pathogenic mutations in patients with parathyroid dysfunction. Regulation of PTH gene expression occurs in part through protein binding to a specific 26 nucleotide instability element in the 3'-UTR of PTH mRNA, in a sequence-dependent manner. Thus, the PTH 3'-UTR has emerged as an important potential contributor to parathyroid dysfunction. Therefore, we sought to rigorously examine the PTH 3'-UTR in patients with primary and secondary parathyroid disorders, including primary parathyroid hyperplasia, secondary parathyroid hyperplasia, sporadic parathyroid adenoma and familial hypoparathyroidism of unknown genetic basis. Twenty-one parathyroid glands from 14 patients with primary parathyroid hyperplasia, 40 sporadic parathyroid adenomas from 40 patients, 42 parathyroid glands from 29 patients with secondary parathyroid hyperplasia and peripheral blood leucocytes from 24 affected members of eight kindreds with familial hypoparathyroidism of unknown genetic basis were examined for mutations in the 3'-UTR of the PTH gene. No alterations from the normal sequence were detected in any of the 127 samples examined. Based on the absence of identifiable DNA sequence alterations in these forms of parathyroid dysfunction, it is unlikely that mutation of the PTH 3'-UTR contributes frequently to their pathogenesis.