Revised 14.7-cM locus for the hyperparathyroidism-jaw tumor syndrome gene, HRPT2.
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ABSTRACT:
SUBMITTER: Hobbs MR
PROVIDER: S-EPMC447614 | biostudies-literature | 2002 May
REPOSITORIES: biostudies-literature
Publications
Revised 14.7-cM locus for the hyperparathyroidism-jaw tumor syndrome gene, HRPT2.
Hobbs Maurine R MR Rosen Irving B IB Jackson Charles E CE
American journal of human genetics 20020501 5
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Project description: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. Some families have had affected members with involvement of the kidneys, variously reported as Wilms tumors, nephroblastomas, and hamartomas. The HPT-JT gene (HRPT2) maps to chromosome 1q25-q31. We describe further investigation of two HPT-JT families (K3304 and K3349) identified through the literature. These two expanded families and two previously reported families were investigated jointly for linkage with 21 new, closely linked markers. Multipoint linkage analysis resulted in a maximum LOD score of 7.83 (at recombination fraction 0) for markers D1S2848-D1S191. Recombination events in these families reduced the HRPT2 region to approximately 14.7 cM. In addition, two of these four study families (i.e., K3304 and K11687) share a 2.2-cM length of their (expanded) affected haplotype, indicating a possible common origin. Combining the linkage data and shared-haplotype data, we propose a 0.7-cM candidate region for HRPT2.
| S-EPMC1377760 | biostudies-other
Project description: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. This syndrome is clinically and genetically distinct from other endocrine neoplasia syndromes and appears to result from mutation of an endocrine tumor gene designated "HRPT2." We studied five HPT-JT families (59 persons, 20 affected); using PCR-based markers, we instituted a genomewide linkage search after excluding several candidate genes. Lod scores were calculated at various recombination fractions (theta), penetrance 90%. We mapped HRPT2 to the long arm of chromosome 1 (1q21-q31). The maximal lod score was 6.10 at theta = .0 with marker D1S212, or > 10(6) odds in favor of linkage. In six hereditary Wilms tumor families (96 persons, 29 affected), we found no linkage to 1q markers closely linked with HRPT2 (lod scores -15.6 [D1S191] and -17.8 [D1S196], theta = .001). Nine parathyroid adenomas and one Wilms tumor from nine members of three HPT-JT families were examined for loss of heterozygosity at linked loci. The parathyroid adenomas and Wilms tumor showed no loss of heterozygosity for these DNA markers. Our data establish that HRPT2, an endocrine tumor gene on the long arm of chromosome 1, is responsible for the HPT-JT syndrome but not for the classical hereditary Wilms tumor syndrome.
| S-EPMC1801214 | biostudies-other
Project description:BackgroundPrimary hyperparathyroidism (PHPT) is a relatively rare disorder among children, adolescents and young adults. Its development at an early age is suspicious for hereditary causes, though the need for routine genetic testing remains controversial.ObjectiveTo identify and describe hereditary forms of PHPT in patients with manifestation of the disease under 40 years of age.DesignWe enrolled 65 patients with PHPT diagnosed before 40 years of age. Ten of them had MEN1 mutation, and PHPT in them was the first manifestation of multiple endocrine neoplasia type 1 syndrome.MethodsThe other fifty-five patients underwent next-generation sequencing (NGS) of a custom-designed panel of genes, associated with PHPT (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D). In cases suspicious for gross CDC73 deletions multiplex ligation-dependent probe amplification was performed.ResultsNGS revealed six pathogenic or likely pathogenic germline sequence variants: four in CDC73 c.271C>T (p.Arg91*), c.496C>T (p.Gln166*), c.685A>T (p.Arg229*) and c.787C>T (p.Arg263Cys); one in CASR c.3145G>T (p.Glu1049*) and one in MEN1 c.784-9G>A. In two patients, MLPA confirmed gross CDC73 deletions. In total, 44 sporadic and 21 hereditary PHPT cases were identified. Parathyroid carcinomas and atypical parathyroid adenomas were present in 8/65 of young patients, in whom CDC73 mutations were found in 5/8.ConclusionsHereditary forms of PHPT can be identified in up to 1/3 of young patients with manifestation of the disease at <40 years of age. Parathyroid carcinomas or atypical parathyroid adenomas in young patients are frequently associated with CDC73 mutations.
| S-EPMC5633061 | biostudies-literature
Project description:BackgroundHyperparathyroidism jaw-tumor syndrome (HPT-JT) is the rarest familial cause of primary hyperparathyroidism, with an incidence <1/1000000, caused by a pathogenic variant in the CDC73 (or HRPT2) gene that encodes parafibromin, a protein involved in many cellular mechanisms. Patients with HPT-JT have a 15-20% of risk of developing parathyroid carcinoma, whereas it accounts for only 1% of all cases of primary hyperparathyroidism. Patients also develop jaw tumors in 30% of cases, kidney abnormalities in 15% of cases, and uterine tumors in 50% of patients.Case reportHere are report two atypical cases of HPT-JT with variable expressivity in the same family. In front of an isolated primary hyperparathyroidism at 28 years of age of incidental discovery following a weight gain, the propositus benefited a first-line panel by Next-Generation Sequencing of the genes involved in familial hyperparathyroidism: CaSR, CDC73, MEN1, and RET. Genetic testing revealed the presence of a pathogenic germline variation CDC73: c.687_688dup; p.Val230Glufs*28, found only in nine families in the literature and allowing the diagnosis of HPT-JT. Given a history of primary hyperparathyroidism at 52 years and adenomyosis, the patient's mother also underwent a genetic analysis that found her daughter's variation and established her inherited trait.ConclusionIn view of the clinical and genotypic heterogeneity, we confirm the interest of using an extended gene panel for the diagnosis of familial primary hyperparathyroidism. CDC73 variations could be more frequent than described in the literature. The association of primary hyperparathyroidism with uterine involvement could be a new indication for analysis.
| S-EPMC10178793 | biostudies-literature
Project description:Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by parathyroid tumors in association with fibro-osseous jaw tumors and uterine and renal lesions. HPT-JT syndrome is caused by germline mutations of the cell division cycle 73 (CDC73) gene that encodes the parafibromin, a 531-amino acid protein with antiproliferative activity. Primary hyperparathyroidism is the main finding of HPT-JT syndrome, usually caused by a single-gland parathyroid involvement (80% of cases), at variance with other variants of hereditary hyperparathyroidism, in which a multiglandular involvement is more frequent. Moreover, parathyroid carcinoma may occur in approximately 20% of cases. Surgery is the treatment of choice for primary hyperparathyroidism, but the extent of surgery remains controversial, varying between bilateral neck and focused exploration, with subtotal or limited parathyroidectomy. Recently, more limited approaches and parathyroid excisions have been suggested in order to decrease the risk of permanent hypoparathyroidism, the main surgical morbidity following more extensive surgical approaches. Ossifying fibromas of the mandible or maxilla may present only in a minority of cases and, even if benign, they should be surgically treated to avoid tumor growth and subsequent functional limitations. Benign and malignant uterine involvement (including leiomyomas, endometrial hyperplasia, adenomyosis, multiple adenomyomatous polyps, and adenosarcomas) is the second most common clinical feature of the syndrome, affecting more than 50% of CDC73-carrier women. Genetic testing should be performed in all family members of affected individuals, in young patients undergoing surgery for primary hyperparathyroidism, or in presence of other associated tumors, allowing early diagnosis and prompt treatment with more tailored surgery. Moreover, CDC73 mutation carriers should be also periodically screened for primary hyperparathyroidism and the other associated tumors. The present review was aimed to summarize the main clinical features of HPT-JT syndrome, focusing on genetic screening and surgical treatment, and to revise the available literature.
| S-EPMC6935818 | biostudies-literature
Project description:The hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a familial cancer syndrome that can result from germline inactivation of HRPT2/CDC73, a putative tumor suppressor gene that encodes parafibromin, a component of the transcriptional regulatory PAF1 complex with homology to the yeast protein Cdc73p. The vast majority of HRPT2/CDC73 germline mutations identified have been truncation or frameshift mutations, and loss of function due to missense mutation is rare. We report here a kindred with HPT-JT due to a germline L95P missense mutation in parafibromin. The mutant parafibromin was studied in vitro to understand the basis of its presumed loss-of-function. When transfected in cultured cells, the L95P mutant was expressed to a lower level than wild-type (wt) parafibromin, a difference that was not overcome by inhibition of the proteasomal degradation pathway. The L95P mutant parafibromin retained the ability to assemble with endogenous PAF1 complex components as evidenced by co-immunoprecipitation. Analysis of subcellular localization showed that the L95P mutant was markedly deficient in nucleolar localization compared to the wt, an impairment likely resulting from disruption of a putative nucleolar localization signal immediately upstream of the L95P mutation. Transfection of the L95P parafibromin mutant, but not the wt, enhanced cell cycle progression and increased cell survival in NIH-3T3 and HEK 293 cells, resulting apparently from dominant interference with endogenous parafibromin action. The simultaneous loss of nucleolar localization and acquisition of a growth stimulatory phenotype with the L95P mutation raise the possibility that parafibromin must interact with targets in the nucleolus to fully execute its tumor suppressor functions.
| S-EPMC3098453 | biostudies-literature
Project description:Inactivating mutations of CDC73 cause Hyperparathyroidism-Jaw Tumour syndrome (HPT-JT), Familial Isolated Hyperparathyroidism (FIHP) and sporadic parathyroid carcinoma. We conducted CDC73 mutation analysis in an HPT-JT family and confirm carrier status of the proband's daughter.The proband had primary hyperparathyroidism (parathyroid carcinoma) and uterine leiomyomata. Her father and daughter had hyperparathyroidism (parathyroid adenoma) but no other manifestations of HPT-JT. CDC73 mutation analysis (sequencing of all 17 exons) and whole-genome copy number variation (CNV) analysis was done on leukocyte DNA of the three affecteds as well as the proband's unaffected sister.A novel deletion of exons 4 to 10 of CDC73 was detected by CNV analysis in the three affecteds. A novel insertion in the 5'UTR (c.-4_-11insG) that co-segregated with the deletion was identified. By in vitro assay the 5'UTR insertion was shown to significantly impair the expression of the parafibromin protein. Screening for the mutated CDC73 confirmed carrier status in the proband's daughter and the biochemistry and ultrasonography led to pre-emptive surgery and resolution of the hyperparathyroidism.A novel gross deletion mutation in CDC73 was identified in a three-generation HPT-JT family emphasizing the importance of including screening for large deletions in the molecular diagnostic protocol.
| S-EPMC5543551 | biostudies-other
Project description:Background:Primary hyperparathyroidism usually occurs secondary to parathyroid adenoma, multiglandular hyperplasia, or parathyroid carcinoma. The patients usually present with incidentally discovered high calcium level and systemic or skeletal manifestations. In young patients with primary hyperparathyroidism, familial syndromes including multiple endocrine neoplasia types 1, 2, and 4 and hyperparathyroidism jaw tumor syndrome should be considered. Case Description. We present a case of a 22-year-old Sri Lankan woman who presented with femur fractures in a background of childhood nephroblastoma and maxillary fibro-osseous tumor. The patient had biochemical parameters suggestive of primary hyperparathyroidism with a parathyroid mass. The histology following excision of the mass revealed a parathyroid adenoma. Based on the associated clinical manifestations, hyperparathyroidism jaw tumor syndrome was suspected, and genetic studies reported a positive CDC73 mutation with a whole-gene deletion of exon 1-17. Conclusion:Hyperparathyroidism jaw tumor syndrome is an important diagnosis to consider in a young patient presenting with classic clinical features due to the risk of malignancy, familial involvement, and need to monitor for progressive systemic manifestations. As this is a rare disease, it can often be missed due to low degree of suspicion and the ability of the jaw tumor to mimic a metastatic deposit.
| S-EPMC7102458 | biostudies-literature
Project description:CDC73/Parafibromin is a critical component of the Paf1 complex (PAF1C), which is involved in transcriptional elongation and histone modifications. Mutations of the human CDC73/HRPT2 gene are associated with hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant disorder. CDC73/parafibromin was initially recognized as a tumor suppressor by inhibiting cell proliferation via repression of cyclin D1 and c-myc genes. In recent years, it has also shown oncogenic features by activating the canonical Wnt/β-catenin signal pathway. Here, through limited proteolysis analysis, we demonstrate that the evolutionarily conserved human CDC73 N-terminal 111 residues form a globularly folded domain (hCDC73-NTD). We have determined a crystal structure of hCDC73-NTD at 1.02 Å resolution, which reveals a novel protein fold. CDC73-NTD contains an extended hydrophobic groove on its surface that may be important for its function. Most pathogenic CDC73 missense mutations associated with the HPT-JT syndrome are located in the region encoding CDC73-NTD. Our crystal and biochemical data indicate that most CDC73 missense mutations disrupt the folding of the hydrophobic core of hCDC73-NTD, while others such as the K34Q mutant reduce its thermostability. Overall, our results provide a solid structural basis for understanding the structure and function of CDC73 and its association with the HPT-JT syndrome and other diseases.
| S-EPMC5688130 | biostudies-literature
Project description:While somatic disruptive mitochondrial DNA (mtDNA) mutations that severely affect the respiratory chain are counter-selected in most human neoplasms, they are the genetic hallmark of indolent oncocytomas, where they appear to contribute to reduce tumorigenic potential. A correlation between mtDNA mutation type and load, and the clinical outcome of a tumor, corroborated by functional studies, is currently lacking. Recurrent familial oncocytomas are extremely rare entities, and they offer the chance to investigate the determinants of oncocytic transformation and the role of both germline and somatic mtDNA mutations in cancer. We here report the first family with Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome showing the inherited predisposition of four individuals to develop parathyroid oncocytic tumors. MtDNA sequencing revealed a rare ribosomal RNA mutation in the germline of all HPT-JT affected individuals whose pathogenicity was functionally evaluated via cybridization technique, and which was counter-selected in the most aggressive infiltrating carcinoma, but positively selected in adenomas. In all tumors different somatic mutations accumulated on this genetic background, with an inverse clear-cut correlation between the load of pathogenic mtDNA mutations and the indolent behavior of neoplasms, highlighting the importance of the former both as modifiers of cancer fate and as prognostic markers.
| S-EPMC8616364 | biostudies-literature