Endocrine Abstracts

Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterised by hypercalcemia, skeletal fragility, and renal stones with majority (75%) of parathyroid tumours localized to the inferior parathyroid glands. The reasons for this natural bias are not known till date. A probable reason may be due to inherent differences in the molecular milieu of normal superior and inferior parathyroid glands. Such questions cannot be answered using superior and inferior parathyroid adenoma tissues from different patients due to the confounding effect of inter-individual differences. Comparison of inferior parathyroid adenoma tissue with normal superior gland from the same patient would also be inappropriate, as any differences observed could be secondary to tumorigenesis. Thus, the ideal approach would be comparison of normal superior and inferior parathyroid glands from the same individual. However, it is difficult to obtain normal parathyroid tissue. To overcome this limitation, we assessed the global gene expression profile of superior and inferior glands obtained from forensic autopsies. Genes with significant differential expression between superior and inferior parathyroids were further confirmed by RT-PCR in 19 pair of glands. As an iterative approach, additional genes with an established role in parathyroid disorders, i.e., CASR, MAFB, PAX9, TBCE, TBX1, VDR, MEN1, CCND1, and CDC73 were also evaluated by RT-PCR in all 19 pairs of superior and inferior parathyroid glands. Seven homeobox genes, namely HOXA4, HOXA5, HOX-BAS3, HOXB4, HOXB6, HOXB9, IRX1, and one encoding for ALDH1A2 showed a lower expression in the inferior parathyroid glands than the superior. Conversely, SLC6A1 showed a higher expression in the inferior glands. Of the nine genes with significant differential mRNA expression among superior and inferior glands HOXB9, HOXB4 and IRX1 could be detected by western blotting/mass spectrometry. The study is the first to provide novel clues for the differential expression of seven Homeobox genes HOXA4, HOXA5, HOX-BAS3, HOXB4, HOXB6, HOXB9, IRX1 along with ALDH1A2, and SLC6A1 in inferior vs the superior parathyroid glands. The Homeobox genes are evolutionarily conserved family of transcriptional-factors essential for embryogenesis and tumorigenesis. The above results suggest that the first hit in parathyroid oncogenesis might be developmental. The mutations in MEN1, CDC73, or CCND1 in the inferior gland may be a second hit. This study suggests potential clues for the preferential localization of parathyroid tumours to the inferior glands as in primary hyperparathyroidism. Future studies on identification of methylations of homebox genes may also help elucidate the underlying mechanisms of primary hyperparathyroidism.