Disease relevance of CDC73

• Each syndrome of parathyroid neoplasia associates with characteristic cancer(s): enteropancreatic neuroendocrine or foregut carcinoid tissues (MEN1), thyroidal C cells (MEN2A), or parathyroid (HPT-JT) [1].
• In light of the strong association between mutations of HRPT2 and sporadic parathyroid carcinoma demonstrated in this study, it is hypothesised that HRPT2 mutation is an early event that may lead to parathyroid malignancy and suggest intragenic mutation of HRPT2 as a marker of malignant potential in both familial and sporadic parathyroid tumours [2].
• In total, seven novel and one previously reported mutation were identified. "Two-hits" (double mutations or one mutation and loss of heterozygosity at 1q24-32) affecting HRPT2 were found in two sporadic carcinomas, two HPT-JT-related and two FIHP related tumours [2].
• Furthermore, our findings likely preclude an adenoma to carcinoma progression model for parathyroid tumorigenesis outside of the presence of either a germ-line or somatic HRPT2 mutation [3].
• A class discovery approach identified three distinct groups: (1) predominantly hyperplasia cluster, (2) HRPT2/carcinoma cluster consisting of sporadic carcinomas and benign and malignant tumors from Hyperparathyroidism-Jaw Tumor Syndrome patients, and (3) adenoma cluster consisting mainly of primary adenoma and MEN 1 tumors [3].
• Two novel HRPT2 point mutations, causing K34Q and R292K changes in parafibromin, were detected in one clear cell carcinoma and one Wilms tumor, respectively [4].

High impact information on CDC73

• The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1 [5].
• HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome [5].
• Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors [5].
• The HPT-JT gene (HRPT2) maps to chromosome 1q25-q31 [6].
• Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disease characterized by the development of multiple parathyroid adenomas and multiple fibro-osseous tumors of the maxilla and mandible [6].

Chemical compound and disease context of CDC73

• All patients resumed their lithium therapy, with 1 of 15 patients developing recurrent hyperparathyroidism 2 years following the first operation; this patient required reexploration, at which time an adenoma was resected [7].

Biological context of CDC73

• Taken together, the results suggest that some of the FIHP are a variant of HPT-JT and that the gene involved is a tumor suppressor gene [8].
• Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome [9].
• In addition the HRPT2 gene on 1q, as well as the proto-oncogenes RET on 10q and PRAD1 on 11q are associated with a subset of parathyroid tumors [10].
• However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred [11].
• We mapped HRPT2 to the long arm of chromosome 1 (1q21-q31) [12].

Anatomical context of CDC73

• The syndrome of hereditary hyperparathyroidism and jaw tumors (HPT-JT) is characterized by inheritance, in an autosomal dominant pattern, of recurrent parathyroid adenomas, fibro-osseous tumors of the mandible and/or maxilla, Wilms tumor, and parathyroid carcinoma [12].
• Parafibromin has also been shown to interact with a histone methyltransferase complex that methylates histone H3 and to inhibit proliferation when overexpressed in mammalian cell lines [13].
• Subcellular fractionation and laser confocal microscopy of normal human parathyroid gland demonstrated expression of parafibromin in both the cytoplasmic and nuclear compartments [14].
• Results: Leukocyte DNA analysis revealed a frameshift mutation in exon 2 of HRPT2 [15].
• We found widespread expression of parafibromin, except in connective tissue, smooth muscle, endothelium and some other types of epithelia (colonic, urinary, tubaric, uterine, thyroid) [16].

Associations of CDC73 with chemical compounds

• In addition, cotransfection data suggest that parafibromin can interact with a histone methyltransferase complex that methylates histone H3 on lysine 4 [17].

Regulatory relationships of CDC73

• Finally, RNAi-induced downregulation of parafibromin promotes entry into S phase, implying a role for parafibromin as an inhibitor of cell cycle progression [18].

Other interactions of CDC73

• Loss of heterozygosity (LOH) of the chromosome 1q region containing the HRPT2 gene and chromosome 11q (MEN1) was determined in the carcinomas [19].
• The cellular function of the HPRT2 gene product, parafibromin, has not been defined yet [18].
• Nine parathyroid adenomas and one Wilms tumor from nine members of three HPT-JT families were examined for loss of heterozygosity at linked loci [12].
• Like the yeast complex, the parafibromin complex associates with the nonphosphorylated and Ser2 and Ser5 phosphorylated forms of the RNA polymerase II large subunit [17].
• We demonstrated, by both gene and protein expression, that Histone 1 Family 2, amyloid beta precursor protein, and E-cadherin are useful markers for parathyroid carcinoma and suggest that the presence of a HRPT2 mutation, whether germ-line or somatic, strongly influences the expression pattern of these 3 genes [3].

Analytical, diagnostic and therapeutic context of CDC73

• Immunofluorescence experiments show that parafibromin is a nuclear protein [17].
• The development of rapid denaturing high performance liquid chromatography mutation scanning of MEN1 and HRPT2 facilitates a molecular diagnosis of the associated familial syndromes for both clinically affected and at-risk family members [20].
• OBJECTIVE: The objective of this study was early diagnosis of parathyroid tumor in a family with germline HRPT2 mutation [21].
• To increase our knowledge of the distribution and patterns of expression of parafibromin, we examined its expression and location in many different mouse and human organs by immunohistochemistry [16].
• Non-morphological techniques, such as Northern and Western blotting and reverse transcriptase-PCR, indicate that parafibromin is ubiquitously expressed, but extensive immunohistochemical studies have not been performed [16].

References