Update on Genetic and Clinical Aspects of Primary Hyperparathyroidism: Update on Genetic and Clinical Aspects of Primary Hyperparathyroidism

S. Miedlich, K. Krohn, R. Paschke

Disclosures

Clin Endocrinol. 2003;59(5) 

In This Article

Identification of the PRAD1 Gene - An Oncogene

The search for clonal abnormalities in parathyroid adenomas led to the identification of tumour cell-specific restriction-fragment-length alterations involving the PTH gene in two of 43 parathyroid adenomas (Arnold et al., 1988). Structural analysis of the PTH gene revealed a rearrangement of the 5' regulatory region from its coding exons and recombination with a novel DNA locus D11S287 in a small subset of benign parathyroid adenomas (Arnold et al., 1989). mRNA transcripts of the breakpoint adjacent gene were identified and found to be dramatically overexpressed in these tumours which led to the conclusion that the rearrangement of the PTH gene regulatory region resulted in activation of a putative oncogene. Subsequent cloning of this gene identified a novel oncogene (PRAD1=parathyroid adenoma 1) which showed sequence similarities with the cyclins (Motokura et al., 1991). The new gene named cyclin D1 has been mapped to chromosome 11q13, whereas the PTH gene is localized on 11p15. Thus, it has been demonstrated here that the rearrangement was caused by a pericentromeric inversion, inv(11)(p15; q13), which brings the 5' PTH regulatory region upstream of the cyclin D1 gene.

Cyclin D1 is a 35-kDa protein with a short half-life of less than 20 min. It is ubiquitously expressed with a peak during the early G1 phase. Cyclins heterodimerize with catalytic subunits, cyclin-dependent kinases (Cdks) to form holoenzymes. Substrates of these cyclin/Cdk complexes which are inactivated upon phosphorylation are for instance the retinoblastoma protein (pRb) and the related proteins, p130 and p107. It is thought that phosphorylation and inactivation of pRb as a known tumour suppressor leads to progression through the cell cycle.

There is a discrepancy between the frequency of the chromosomal rearrangement inv(11)(p15; q13) which has been reported in three of 86 parathyroid tumours (Arnold et al., 1988; Friedman et al., 1990) and the overexpression of cyclin D1 in parathyroid tumours which has been found in 18-40% (Hsi et al., 1996; Tominaga et al., 1999). The divergent results may be caused by undetectable DNA rearrangements (Hsi et al., 1996). However, the precise role of cyclin D1 overexpression in parathyroid tumours has yet to be elucidated. An animal model may provide further clues to the pathogenesis of parathyroid adenomas. Mice harbouring a transgene in which the cyclin D1 gene is placed under the control of the PTH regulatory region, thereby mimicking the rearrangement in parathyroid adenomas, develop hyperparathyroidism by the age of 6-10 months (Imanishi et al., 2001).

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