Cell division cycle protein 73 homolog (CDC73) mutations in the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid tumors

Abstract

ABSTRACT:The hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by the occurrence of parathyroid tumors in association with ossifying fibromas of the maxilla and/or mandible. The gene responsible for HPT-JT, known as CDC73, was identified in 2002 and encodes a 531 amino acid protein known as parafibromin. Parafibromin is predominantly a nuclear protein that interacts directly with b-catenin and also forms part of the RNA polymerase associated factor-1 complex (Paf1C) that regulates transcription. Heterozygous germline CDC73 mutations are detected in the majority of patients with HPT-JT, and the demonstration of loss of heterozygosity (LOH) at the CDC73 locus in tumors from affected individuals is consistent with a tumor suppressor role. Somatic CDC73 mutations are a frequent finding in nonfamilial (i.e., sporadic) parathyroid carcinomas and have also been reported in benign sporadic parathyroid tumors as well as sporadic renal and fibro-osseous jaw tumors. To date, 111 independent CDC73 mutations have been identified (68 germline; 38 somatic; 5 undefined), and these occur throughout the coding region and splice sites of the CDC73 gene, with the majority (480%) predicting premature truncation of the parafibromin protein. These CDC73 mutations, together with their clinical and biological relevance, are reviewed.

Early-onset, severe, and recurrent primary hyperparathyroidism associated with a novel <i>CDC73</i> mutation

“…min protein. There is no phenotype-genotype correlation [21]. To our knowledge, the same mutation as in our case has been reported only in a non-familial case from a French national cohort [17].…”

“…Articles including information on patients' age and serum calcium levels at initial diagnosis were mutation analysis should be considered young patients with PHPT, PHPT with polyglandular involvement of the parathyroid, recurrent PHPT, and severe hypercalcemia due to PTH elevation when testing for MEN1 mutation yields negative results [18]. In addition, CDC73 mutation analysis may be recommended if the following manifestations are present: sporadic parathyroid carcinoma, FIHP, parathyroid adenoma in patients under 35 years old, sporadic ossifying fibroma of the jaw, or parathyroid adenoma plus one or more of early-onset uterine lesions, renal cysts or tumors, pancreatic tumors, and/ or thyroid tumors [21]. PTC was also seen in the present case.…”

Downregulation of CASR expression and global loss of parafibromin staining are strong negative determinants of prognosis in parathyroid carcinoma

“…14 However, exons 1, 2 and 7, which harbor up to 85% of all somatic HRPT2/CDC73 mutations, 12,15,18,28,29 were completely screened in all patients. Silencing of HRPT2/CDC73 because of promoter hypermethylation was also not studied, although this may not be relevant, as it was recently documented that hypermethylation does not have a role in loss of this gene.…”

“…In patients with parathyroid carcinoma, most of the identified HRPT2/CDC73 mutations are predicted to prematurely truncate the parafibromin protein, 12,13,16,28 which often lead to loss of parafibromin staining. Parafibromin is known to be involved in cell transcription, proliferation, differentiation and apoptosis, although the exact mechanism by which this protein increases the malignant potential of parathyroid carcinoma remains to be established.…”

Mouse models for inherited endocrine and metabolic disorders

“…Human parafibromin has been shown to also form part of the Paf1 complex, which associates with RNA polymerase II, and functions in: H3K4 methylation via interaction with methyltransferase complexes (RozenblattRosen et al 2005); chromatin remodelling and initiation of transcription (Newey et al 2009). Heterozygous HRPT2 mutations have been identified in HPT-JT patients and some patients with familial isolated hyperparathyroidism, and HPT-JT-associated parathyroid tumours have been reported to have allelic deletions or point mutations of HRPT2 (Newey et al 2010). Furthermore, some HPT-JT-causing missense and nonsense mutant parafibromin proteins lead to a loss of interactions with the Paf1 and methyltransferase complexes .…”