Identification of the genes reponsible for syndromes of inherited neoplasia frequently provides insight into critical pathways governing cellular growth, proliferation and signalling. Approximately 5% of primary hyperparathyroidism (HPT) is familial in nature, though many of the causative genes remain unrecognized. Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a familial syndrome of HPT with autosomal dominant transmission and high but incomplete penetrance. The major features are HPT (90%) including 15% of all affected by HPT-JT with parathyroid cancer, jaw tumors (30%), bilateral renal cysts (10%), and less commonly solid renal tumors. Nearly 10% of adult cases appear to be silent carriers. The trait links to the HRPT2 locus at 1q25-q31. The Metabolic Diseases Branch participated in an international collaborative effort to identify the gene responsible for HPT-JT on the long arm of chromosome 1. The region on chromosome 1 was refined to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, thirteen different heterozygous, germline, inactivating mutations were identified in a single gene in fourteen 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 three 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. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which the name parafibromin was proposed. These 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.

Project Start
Project End
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Budget End
Support Year
2
Fiscal Year
2003
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
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Country
United States
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Sharretts, John M; Kebebew, Electron; Simonds, William F (2010) Parathyroid cancer. Semin Oncol 37:580-90
Simonds, William F (2007) Ruling out a suspect: the role of beta-catenin mutation in benign parathyroid neoplasia. J Clin Endocrinol Metab 92:1235-6
Marx, Stephen J; Simonds, William F (2006) Editorial: Imaging to detect early endocrine cancers. J Clin Endocrinol Metab 91:2861-3
Kelly, Thomas G; Shattuck, Trisha M; Reyes-Mugica, Miguel et al. (2006) Surveillance for early detection of aggressive parathyroid disease: carcinoma and atypical adenoma in familial isolated hyperparathyroidism associated with a germline HRPT2 mutation. J Bone Miner Res 21:1666-71
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Woodard, Geoffrey E; Lin, Ling; Zhang, Jian-Hua et al. (2005) Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression. Oncogene 24:1272-6
Pidasheva, Svetlana; Canaff, Lucie; Simonds, William F et al. (2005) Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia. Hum Mol Genet 14:1679-90
Marx, Stephen J; Simonds, William F (2005) Hereditary hormone excess: genes, molecular pathways, and syndromes. Endocr Rev 26:615-61
Simonds, William F; Robbins, Christiane M; Agarwal, Sunita K et al. (2004) Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab 89:96-102
Weinstein, Lee S; Simonds, William F (2003) HRPT2, a marker of parathyroid cancer. N Engl J Med 349:1691-2

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