Hyperparathyrodism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder. Loss of function of the cell division cycle protein 73 homolog (CDC73) gene is responsible for the syndrome. This gene encodes an ubiquitously expressed 531 amino acid protein, parafibromin, that acts as a tumor suppressor. Loss of heterozygosity (LOH) of the CDC73 locus in many HPT-JT associated parathyroid tumors from patients with germline mutation is in accordance with Knudson's "two-hit" model for hereditary cancer. A 41-year-old man with mandible ossifying fibroma suffered from severe hypercalcemia due to parathyroid carcinoma (PC). Genetic analysis was performed to evaluate germinal and somatic CDC73 gene mutation as well as real-time qRT-PCR to quantify CDC73 mRNA, miR-155 and miR-664 expression levels. Immunohistochemistry and Western blotting (WB) assay were carried out to evaluate parafibromin protein expression. A novel heterozygous nonsense mutation, c.191-192 delT, was identified in the CDC73 gene. No CDC73 LOH was found in PC tissue, nor any differences in expression levels for CDC73 gene, miR-155 and miR-664 between PC and parathyroid adenoma control tissues. On the contrary, both immunohistochemistry and WB assay showed an approximate 90% reduction of parafibromin protein expression in PC. In conclusion, this study describes a novel germinal mutation, c.191-192 delT, in the CDC73 gene. Despite normal CDC73 gene expression, we found a significant decrease in parafibromin. We hypothesize that a gene silencing mechanism, possibly induced by microRNA, could play a role in determining somatic post-transcriptional inactivation of the wild type CDC73 allele.
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http://dx.doi.org/10.1507/endocrj.EJ18-0387 | DOI Listing |
JBMR Plus
January 2025
Department of Medicine, Division of Endocrinology, Stanford University, Stanford, CA 94305, United States.
Germline and somatic pathogenic variants in the gene, encoding the nuclear protein parafibromin, increase the risk for parathyroid carcinoma and cause hereditary primary hyperparathyroidism (PHPT) syndromes known as familial isolated hyperparathyroidism (FIHP) and hyperparathyroidism-jaw tumor syndrome (HPT-JT). The identification of pathogenic germline variants in PHPT-susceptibility genes can influence surgical planning for parathyroidectomy, guide screening for potential syndromic manifestations, and identify/exonerate at-risk family members. Numerous types of pathogenic germline variants have been described for -related conditions, including deletion, truncating, missense, and splice site mutations.
View Article and Find Full Text PDFCureus
November 2024
Maxillofacial Surgery, King Hussein Medical Center, Amman, JOR.
Hyperparathyroidism is a common endocrinopathy classified into three subtypes: primary, secondary, and tertiary. One of the rare symptoms that patients with hyperparathyroidism present is the formation of osteolytic lesions of the jaws. Brown tumors are rare skeletal osteolytic masses of a poorly understood etiology.
View Article and Find Full Text PDFCancers (Basel)
November 2024
Department of Oncology-Pathology, Karolinska Institutet, 17164 Stockholm, Sweden.
Background: The etiology of most mesenchymal tumors is unknown, and knowledge about syndromes with an increased risk of tumors in bone or soft tissue is sparse.
Methods: We present a prospective germline analysis of 312 patients with tumors suspected of being sarcomas at a tertiary sarcoma center. Germline and tumor whole genome sequencing, tumor transcriptome, and methylome analyses were performed.
Int J Mol Sci
October 2024
Bone Metabolism Diseases and Diabetes Unit, IRCCS Istituto Auxologico Italiano, 20145 Milan, Italy.
Pathol Res Pract
November 2024
Department of Oral pathology and Microbiology, Centre for dental education and research, All India Institute of Medical Sciences, New Delhi, India. Electronic address:
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