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

Inactivation of the MEN1 Gene - A Putative Tumour Suppressor Gene

The most frequently reported chromosomal abnormality in parathyroid adenomas is loss of heterozygosity (LOH) on 11q. Therefore, it has been proposed that this region may harbour at least one tumour suppressor gene which could be responsible for monoclonal cell expansions in the parathyroid glands. Identification of the MEN1 gene at this genetic location (11q13) by positional cloning (Chandrasekharappa et al., 1997) initiated the search for somatic mutations in this gene in sporadic endocrine neoplasms. Somatic mutations within the MEN1 gene have been detected in up to 27% of sporadic parathyroid adenomas (Heppner et al., 1997; Carling et al., 1998; Farnebo et al., 1998; Miedlich et al., 2000). Moreover, in a series of 19 monoclonal parathyroid tumours we could detect a somatic MEN1 gene mutation in 26%. Evidence of clonal expansion of cells with a MEN1 gene mutation and the physiological consequences of a mutation in this tumour suppressor gene infers that this genetic variation is an important step in the development of these parathyroid tumours (Miedlich et al., 2000).

Two findings indicate that the gene product menin may function as a tumour suppressor. First, approximately 85% of these mutations are inactivating mutations (deletion and nonsense mutations) leading to premature protein truncation (for review see Thakker, 1998). Second, LOH on chromosome 11q13 has been reported in parathyroid tumours with MEN1 gene mutations (Heppner et al., 1997; Carling et al., 1998; Farnebo et al., 1998). According to Knudson's hypothesis (Knudson, 1971), inactivation of a tumour suppressor only occurs after mutation in one allele and loss of the wild-type allele.

Menin, the MEN1 gene product, was found to localize to the nucleus, with two independent nuclear localization signals (Guru et al., 1998). Functional studies by yeast two-hybrid screen identified the AP1 (activator protein 1) transcription factor JunD as an interacting partner of menin (see Fig. 2). Menin represses JunD-mediated transcriptional activation. More recently, other interacting partners of menin (homeobox-containing protein Pem, nm23/nucleoside diphosphate kinase, Smad3, NF-κB protein) have been identified which point to a role in gametogenesis, cell developmentand cell growth (Heppner et al., 2001; Kaji et al., 2001; Lemmens et al., 2001; Ohkura et al., 2001). However, the precise mechanisms by which inactivation of menin initiates tumourigenesis in endocrine cells remains to be elucidated. A knockout model of the MEN1 gene in mice showing a very similar phenotype to MEN-1 may provide further clues to the development of endocrine neoplasms by inactivation of the MEN1 gene (Crabtree et al., 2001).

Schematic illustration of the proposed/hypothetical role of cyclin D1 and menin within the cell cycle. Cdk 4/6, cyclin-dependent kinases; Ink4, Cip/Kip, cyclin-dependent kinase inhibitors; pRb, retinoblastoma protein; M, mitosis; S, DNA synthesis.

For 46-69% of the tumours with LOH on 11q, a somatic MEN1 gene mutation could be identified as the underlying genetic defect(Heppner et al., 1997; Carling et al., 1998; Farnebo et al., 1998; Dwight et al., 2000). However, the high prevalence of allelic losses at this location and the lack of MEN1 gene mutations in more than 31% of sporadic parathyroid adenomas with LOH on 11q implies the presence of other tumour suppressor genes awaiting to be identified.

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