Alternative titles; symbols
HGNC Approved Gene Symbol: CDC73
SNOMEDCT: 128474007, 255037004, 363481002, 702378002;
Cytogenetic location: 1q31.2 Genomic coordinates (GRCh38) : 1:193,122,031-193,254,815 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q31.2 | Hyperparathyroidism-jaw tumor syndrome | 145001 | Autosomal dominant | 3 |
| Hyperparathyroidism, familial primary | 145000 | Autosomal dominant | 3 | |
| Parathyroid adenoma with cystic changes | 145001 | Autosomal dominant | 3 | |
| Parathyroid carcinoma | 608266 | 3 |
Parafibromin (CDC73), LEO1 (610507), PAF1 (610506), and CTR9 (609366) form the PAF protein complex, which associates with the RNA polymerase II subunit POLR2A (180660) and with a histone methyltransferase complex (Rozenblatt-Rosen et al., 2005).
A single locus associated with hyperparathyroidism-2 (HRPT2, HPT-JT; 145001) had been mapped to a 15-cM region within 1q24-q32. Carpten et al. (2002) further refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds and identified the HRPT2 (CDC73) gene using a positional candidate approach. The HRPT2 open reading frame of 1,596 nucleotides encodes a protein of 531 amino acids. Northern blot analysis detected a 2.7-kb transcript expressed at varying levels in all tissues examined. HRPT2 and its encoded protein, which they named parafibromin, are evolutionarily conserved; human parafibromin shares 54% and 25% identity with the D. melanogaster and C. elegans orthologs, respectively.
By SDS/PAGE, Rozenblatt-Rosen et al. (2005) determined that endogenous human parafibromin has an apparent molecular mass of 64 kD. Epitope-tagged parafibromin was expressed as a nuclear protein in transfected HeLa cells.
Carpten et al. (2002) determined that the HRPT2 gene contains 17 exons, all of which are coding.
By analyzing proteins that coimmunoprecipitated with parafibromin from the 293T human embryonic kidney cell line, Rozenblatt-Rosen et al. (2005) determined that parafibromin is a subunit of the PAF protein complex. The immunoprecipitate also contained POLR2A that was unphosphorylated, phosphorylated on ser5, or phosphorylated on ser2, suggesting that the PAF complex may be involved in both initiation and elongation. By examining parafibromin truncation mutations found in patients with hyperparathyroidism-jaw tumor syndrome (HRPT2; 145001), Rozenblatt-Rosen et al. (2005) localized a region between amino acids 226 and 413 that was responsible for binding other members of the PAF complex. Some, but not all, of the HRPT2 mutations were defective in binding other subunits. The antiparafibromin immunoprecipitate also associated with a histone methyltransferase complex (see SET7, 606594) and specifically methylated histone H3 on lys4.
The Wnt/Wg pathway (see 164820) controls cell fate, tissue homeostasis, and tumorigenesis, and its activation entails association of beta-catenin (CTNNB1; 116806) with nuclear TCF/LEF proteins (see 153245), resulting in transcriptional activation of target genes. Mosimann et al. (2006) identified parafibromin as the human ortholog of Drosophila hyrax (hyx), a component of the Wnt/Wg signaling pathway. Overexpression of parafibromin increased Wnt signaling, whereas knockdown of parafibromin via small interfering RNA decreased Wnt signaling, in transfected HEK293T cells. Immunoprecipitation analysis of HEK293T and HeLa cells, as well as mouse embryonic fibroblasts, showed that endogenous beta-catenin and parafibromin, as well as other components of the PAF complex, interacted in vivo. Yeast 2-hybrid and protein pull-down assays revealed that repeat 12 and the C-terminal domain of beta-catenin interacted with an evolutionarily conserved N-terminal region centered on amino acids 218 to 263 of parafibromin. Experiments using RNA interference and mutant proteins showed that parafibromin function in Wnt signaling depended on BCL9 (602597) and PYGO (606902), and parafibromin and beta-catenin coprecipitated with BCL9 and PYGO in transfected HEK293T cells. Mosimann et al. (2006) concluded that beta-catenin assembles a nuclear Wnt signaling complex containing BCL9, PYGO, and parafibromin, and that the transcriptional output of beta-catenin depends on the concomitant activities of PYGO and the PAF complex, which is engaged by beta-catenin through parafibromin.
Carpten et al. (2002) found 13 different heterozygous germline inactivating mutations in the HRPT2 gene in 14 families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified 3 somatic inactivating mutations, all located in exon 1. None of these mutations was detected in normal controls, and all were predicted to cause deficient or impaired protein function. The results of Carpten et al. (2002) suggested 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. As parathyroid tumors are malignant at a higher frequency in HPT-JT than in MEN1 (131100) or MEN2 (170400), mutations in HRPT2 are probably an important factor in increased risk of parathyroid carcinoma (608266).
Shattuck et al. (2003) directly sequenced the full coding and flanking splice-junctional regions of the HRPT2 gene in 21 parathyroid carcinomas from 15 patients who had no known family history of primary hyperparathyroidism (145000) or the HPT-JT syndrome at presentation. Parathyroid carcinomas from 10 of the 15 patients had HRPT2 mutations, all of which were predicted to inactivate the encoded parafibromin protein. Two distinct HRPT2 mutations were found in tumors from 5 patients, and biallelic inactivation as a result of a mutation and loss of heterozygosity was found in 1 tumor. At least one HRPT2 mutation was demonstrably somatic in carcinomas from 6 patients. Unexpectedly, HRPT2 mutations in the parathyroid carcinomas of 3 patients were identified as germline mutations.
Howell et al. (2003) detected somatic HRPT2 mutations in 4 of 4 sporadic parathyroid carcinoma samples, and germline mutations were found in 5 of 5 HPT-JT parathyroid tumors (in 2 families) and 2 parathyroid tumors from 1 family with familial isolated primary hyperparathyroidism. 'Two hits'--either double mutations or 1 mutation and loss of heterozygosity at 1q24-q32--affecting HRPT2 were found in 2 sporadic carcinomas. The findings suggested that HRPT2 mutation is an early event that may lead to parathyroid malignancy and that intragenic mutation of HRPT2 may be a marker of malignant potential in both familial and sporadic parathyroid tumors.
By loss of heterozygosity analysis and direct sequencing, Cetani et al. (2004) searched for HRPT2 mutations in 1 kindred with HPT-JT, 3 kindreds with familial isolated primary hyperparathyroidism (FIHP; 145000 and 145001), 7 patients with sporadic parathyroid cancer, and 35 with parathyroid adenomas. A germline heterozygous mutation was found in the donor splice site of intron 1 in 1 of the 3 FIHP families (607393.0010). A somatic HRPT2 mutation was found in 4 of 7 patients with parathyroid cancer. Two of 7 patients with sporadic parathyroid cancer had germline mutations. Four adenomas showed loss of heterozygosity at HRPT2, whereas a somatic HRPT2 mutation was found in 1. Cetani et al. (2004) concluded that their results confirmed the need for testing the HRPT2 gene in FIHP families.
In a kindred with hyperparathyroidism-jaw tumor syndrome (HRPT2; 145001), Carpten et al. (2002) found a met1-to-ile (M1I) heterozygous germline mutation in the HRPT2 gene resulting from a 3G-A transition in exon 1.
Carpten et al. (2002) found a nonsense mutation, arg9 to ter (R9X), in parafibromin as the cause of hyperparathyroidism-jaw tumor syndrome (HRPT2; 145001). The amino acid change resulted from a C-to-T transition at nucleotide 25 of the HRPT2 gene.
In a kindred with hyperparathyroidism-jaw tumor syndrome (HRPT2; 145001), Carpten et al. (2002) found affected individuals had a 41-bp duplication/insertion in exon 1 of the HRPT2 gene, causing frameshift.
Among the 13 different heterozygous germline inactivating mutations in the HRPT2 gene found in 14 families with hyperparathyroidism-jaw tumor syndrome (HRPT2; 145001) by Carpten et al. (2002), there was only 1 recurrent mutation, 679insAG in exon 7, causing a frameshift. This mutation was found in 2 independently identified, seemingly unrelated families who were later found to share an identical disease haplotype through the entire 26-marker interval, suggesting that these individuals had a common ancestor.
In a direct sequencing study of 21 parathyroid carcinomas from 15 patients who had no known family history of primary hyperparathyroidism (HRPT1; 145000) or the HPT-JT syndrome at presentation, Shattuck et al. (2003) found a germline 679insAG mutation and a tumor-specific somatic HRPT2 mutation in the other allele (Y54X; 607393.0008). The insertion was in exon 7 and was predicted to cause a frameshift at amino acid 227 with a stop codon at 257.
Simonds et al. (2004) investigated 32 families with FIHP to determine the frequency of occult mutation in HRPT2, the gene causing HPT-JT. All families had negative clinical testing for MEN1 (131100), hypocalciuric hypercalcemia (145980), and HPT-JT and negative mutational screening of MEN1 and the gene encoding the calcium-sensing receptor (CASR; 601199). The families were characterized by young probands (42 +/- 3 years) and occasionally unusual parathyroid histology, including 4 families with 1 case of parathyroid cancer. Among the 32 FIHP families, only a single one was found to have a mutation in HRPT2 (679insAG); this mutation predicts premature termination of its gene product, parafibromin, and thus its presumed inactivation.
In a family with isolated hyperparathyroidism (HRPT1; 145000), who showed familial occurrence only of primary hyperparathyroidism and showed linkage to 1q24-q32 but not to MEN1 (613733), Carpten et al. (2002) found a trp43-to-ter (W43X) mutation in the HRPT2 gene in a parathyroid tumor (608266). Loss of heterozygosity (LOH) at 1q had been reported in tumors from some kindreds affected with HPT-JT (145001) in whom Carpten et al. (2002) identified germline mutations in their study, suggesting that biallelic inactivation of HRPT2 is associated with HPT-JT. These findings are in agreement with inactivation of a tumor suppressor gene in that region. The frequency of demonstrated LOH at 1q in parathyroid tumors related to HPT-JT is relatively low, especially compared with LOH of MEN1, which is inactivated in more than 70% of the associated parathyroid tumors. It may be that a small mutation in the HRPT2 gene is the second event giving rise to parathyroid tumors related to HPT-JT.
In a kindred with familial isolated hyperparathyroidism (HRPT1; 145000), Carpten et al. (2002) found a germline leu64-to-pro (L64P) mutation in exon 2 of the HRPT2 gene.
In a sporadic parathyroid adenoma with cystic change (see 145001), Carpten et al. (2002) found a somatic 1-bp deletion, 53delT, in exon 1 of the HRPT2 gene, causing frameshift.
In a study of 21 parathyroid carcinomas (608266) from 15 patients who had no known family history of primary hyperparathyroidism (see 145000) or the HPT-JT syndrome (145001) at presentation, Shattuck et al. (2003) identified 1 patient who had a germline frameshift mutation, 679insAG, on 1 allele (607393.0004) and a tumor-specific somatic HRPT2 mutation in the other allele: 162C-G in exon 2, creating a stop codon tyr54 to stop (Y54X).
In the primary tumor and a local recurrence of parathyroid carcinoma (608266), Shattuck et al. (2003) found a germline mutation, 373insA in exon 5, predicted to cause frameshift at amino acid 125 and stop codon at 130. No loss of heterozygosity in the HRPT2 gene was identified. The patient was one of a series who had no known family history of primary hyperparathyroidism (see 145000) or the HPT-JT syndrome (145001) at presentation.
In the proband and 2 affected members of a family with familial isolated hyperparathyroidism (HRPT1; 145000), Cetani et al. (2004) identified heterozygosity for a germline G-to-A transition in the donor splice site of intron 1 of the HRPT2 gene. This mutation was also found as a somatic change in a sporadic parathyroid adenoma (see 145000).
In 6 Roma families from Portugal with hyperparathyroidism-jaw tumor syndrome (HRPT2; 145001), Cavaco et al. (2004) identified a 2-bp deletion in exon 8 of the HRPT2 gene (either TG involving codons 255 and 256 or GT involving codon 256) in 11 affected individuals. The mutation was also found in 19 of 45 asymptomatic individuals (age range, 12 to 74 years) who shared the affected haplotype, suggesting a low age-related penetrance for HPT-JT in these families. The mutation was predicted to lead to a frameshift encoding 9 missense amino acids followed by a premature stop at codon 265. Haplotype analysis suggested that the families were likely to be related through a recent common ancestor.
In a 40-year-old male who had previously been treated for parathyroid atypical adenoma (see 145000), Guarnieri et al. (2006) identified a germline frameshift mutation in exon 7 (685delAGAG) of the HRPT2 gene, predicting a premature stop codon at nucleotides 767-769. Nine family members also carried the mutation, of whom 8 had normal serum calcium. Biochemical and ultrasonographic evaluation detected a 27-year-old hypercalcemic carrier niece with an atypical parathyroid adenoma, and a 43-year-old normocalcemic carrier sister was found by ultrasonography to have an extrathyroidal nodule, which proved to be parathyroid carcinoma (608266). Guarnieri et al. (2006) concluded that germline mutations of the HRPT2 gene may be associated with multiple parathyroid neoplasms.
In a Korean family with hyperparathyroidism-jaw tumor syndrome (HRPT2; 145001), Moon et al. (2005) identified a germline mutation in intron 2 of the HRPT2 gene, IVS2-1G-A. RT-PCR and sequencing of the transcripts revealed that this splicing mutation generated alternative splicing errors leading to the formation of 2 different transcripts, one with exon 3 deleted, the other lacking the first 23 bp of exon 3 due to the use of an internal splice acceptor in exon 3. Translation of both transcripts resulted in premature termination. In addition to this germline mutation, Moon et al. (2005) detected 2 somatic mutations of HRPT2 in malignant parathyroid tumors from the affected individuals. The proband carried a 1-bp deletion in exon 1, 85delG, that was predicted to cause premature termination of the protein (607393.0014). The proband's father carried an 18-bp in-frame deletion, 13_30delCTTAGCGTCCTGCGACAG, also in exon 1 (607393.0015). Moon et al. (2005) noted that to the time of their report, all inactivating somatic mutations in HRPT2 have occurred in exon 1.
See 607393.0013 and Moon et al. (2005).
See 607393.0013 and Moon et al. (2005).
Carpten, J. D., Robbins, C. M., Villablanca, A., Forsberg, L., Presciuttini, S., Bailey-Wilson, J., Simonds, W. F., Gillanders, E. M., Kennedy, A. M., Chen, J. D., Agarwal, S. K., Sood, R., and 17 others. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nature Genet. 32: 676-680, 2002. [PubMed: 12434154] [Full Text: https://doi.org/10.1038/ng1048]
Cavaco, B. M., Guerra, L., Bradley, K. J., Carvalho, D., Harding, B., Oliveira, A., Santos, M.-A., Sobrinho, L. G., Thakker, R. V., Leite, V. Hyperparathyroidism-jaw tumor syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene. J. Clin. Endocr. Metab. 89: 1747-1752, 2004. [PubMed: 15070940] [Full Text: https://doi.org/10.1210/jc.2003-031016]
Cetani, F., Pardi, E., Borsari, S., Viacava, P., Dipollina, G., Cianferotti, L., Ambrogini, E., Gazzerro, E., Colussi, G., Berti, P., Miccoli, P., Pinchera, A., Marcocci, C. Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. J. Clin. Endocr. Metab. 89: 5583-5591, 2004. [PubMed: 15531515] [Full Text: https://doi.org/10.1210/jc.2004-0294]
Guarnieri, V., Scillitani, A., Muscarella, L. A., Battista, C., Bonfitto, N., Bisceglia, M., Minisola, S., Mascia, M. L., D'Agruma, L., Cole, D. E. C. Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: implications for cancer surveillance. J. Clin. Endocr. Metab. 91: 2827-2832, 2006. [PubMed: 16720667] [Full Text: https://doi.org/10.1210/jc.2005-1239]
Howell, V. M., Haven, C. J., Kahnoski, K., Khoo, S. K., Petillo, D., Chen, J., Fleuren, G. J., Robinson, B. G., Delbridge, L. W., Philips, J., Nelson, A. E., Krause, U., Hammje, K., Dralle, H., Hoang-Vu, C., Gimm, O., Marsh, D. J., Morreau, H., Teh, B. T. HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. J. Med. Genet. 40: 657-663, 2003. Note: Erratum: J. Med. Genet. 41: 20 only, 2004. [PubMed: 12960210] [Full Text: https://doi.org/10.1136/jmg.40.9.657]
Moon, S.-D., Park, J.-H., Kim, E.-M., Kim, J.-H., Han, J.-H., Yoo, S.-J., Yoon, K.-H., Kang, M.-I., Lee, K.-W., Son, H.-Y., Kang, S.-K., Oh, S.-J., Kim, K.-M., Yoon, S.-J. K., Park, J.-G., Kim. I.-J., Kang, H. C., Hong, S.-W., Kim, K.-R., Cha, B.-Y. A novel IVS2-1G-A mutation causes aberrant splicing of the HRPT2 gene in a family with hyperparathyroidism-jaw tumor syndrome. J. Clin. Endocr. Metab. 90: 878-883, 2005. [PubMed: 15613436] [Full Text: https://doi.org/10.1210/jc.2004-0991]
Mosimann, C., Hausmann, G., Basler, K. Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo. Cell 125: 327-341, 2006. [PubMed: 16630820] [Full Text: https://doi.org/10.1016/j.cell.2006.01.053]
Rozenblatt-Rosen, O., Hughes, C. M., Nannepaga, S. J., Shanmugam, K. S., Copeland, T. D., Guszczynski, T., Resau, J. H., Meyerson, M. The parafibromin tumor suppressor protein is part of a human Paf1 complex. Molec. Cell. Biol. 25: 612-620, 2005. [PubMed: 15632063] [Full Text: https://doi.org/10.1128/MCB.25.2.612-620.2005]
Shattuck, T. M., Valimaki, S., Obara, T., Gaz, R. D., Clark, O. H., Shoback, D., Wierman, M. E., Tojo, K., Robbins, C. M., Carpten, J. D., Farnebo, L.-O., Larsson, C., Arnold, A. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. New Eng. J. Med. 349: 1722-1729, 2003. [PubMed: 14585940] [Full Text: https://doi.org/10.1056/NEJMoa031237]
Simonds, W. F., Robbins, C. M., Agarwal, S. K., Hendy, G. N., Carpten, J. D., Marx, S. J. Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J. Clin. Endocr. Metab. 89: 96-102, 2004. [PubMed: 14715834] [Full Text: https://doi.org/10.1210/jc.2003-030675]