Dental findings in a family with hyperparathyroidism–jaw tumor syndrome and a novel HRPT2 gene mutation

Aldred, Michael J.; Talacko, Anna; Savarirayan, Ravi; Murdolo, Vince; Mills, Alan E.; Radden, B. G.; Alimov, Andrei; Villablanca, Andrea

doi:10.1016/j.tripleo.2005.06.011

Cited by 63 publications

(42 citation statements)

References 21 publications

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“…A similar HRPT2 mutation spectrum has been suggested in FIHP versus HPT-JT. Indeed, an overall analysis of the HRPT2 germline mutations identified by this study together with the 11 previously reported in FIHP (Carpten et al 2002, Howell et al 2003, Cetani et al 2004, Simonds et al 2004, Villablanca et al 2004, Bradley et al 2005a,b, 2006, Guarnieri et al 2006, Kelly et al 2006, Mizusawa et al 2006) reveals that 16.7% are missense mutations as opposed to 9.5% in HPT-JT (Carpten et al 2002, Howell et al 2003, Bradley et al 2005b, Moon et al 2005, Aldred et al 2006, Mizusawa et al 2006, Yamashita et al 2007. Thus, the presence of a missense mutation might explain the absence of an obvious family history in apparently sporadic PHPT patients.…”

Section: Discussionsupporting

confidence: 51%

Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation

Cetani¹,

Pardi²,

Ambrogini³

et al. 2007

Endocr Relat Cancer

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Early onset of primary hyperparathyroidism (PHPT) and multiglandular involvement suggest a familial form in which germline mutation of a PHPT-related gene(s) and a somatic event at the same locus can be often demonstrated. We investigated the involvement of multiple endocrine neoplasia type 1 (MEN1) and HRPT2 genes in a 39-year-old man with recurrent PHPT. PHPT was firstly diagnosed at the age of 21 and the patient had two recurrences separated by extended periods of normocalcemia. This unusual history prompted us to investigate other family members and study the MEN1 and HRPT2 genes. An HRPT2 germline missense mutation in exon 3 (R91P) was found in the index case, which was associated with different HRPT2 somatic alterations in each of the three examined parathyroid tumors. These findings are consistent with Knudson's 'two hit' concept of biallelic inactivation of classical tumor suppressor genes. Screening of 15 asymptomatic relatives was negative for the R91P germline mutation. All the three abnormal parathyroid specimens showed cystic features at histology and were negative for parafibromin immunostaining. In one specimen, diffuse parafibromin staining was evident in a rim of normal parathyroid tissue surrounding the adenomatous lesion. Our study shows that different somatic genetic events at the HRPT2 locus are responsible for the asynchronous occurrence of multiple adenomas in a patient carrying an HRPT2 germline mutation. The finding of diffuse parafibromin staining in a rim of normal parathyroid tissue, but not in the contiguous adenomatous lesion, reinforces the concept that loss of parafibromin expression is responsible for the development of parathyroid tumors in this setting.

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Section: Discussionsupporting

confidence: 51%

Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation

Cetani¹,

Pardi²,

Ambrogini³

et al. 2007

Endocr Relat Cancer

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“…Detected mutations were precisely determined by sequencing at least 10 positive clones after one-step cloning according to a previously published protocol (Aldred et al 2006), and the mutated exons were sequenced in constitutional DNA to confirm the somatic status of the mutation.…”

Section: Mutation Analysis Of the Men1 Genementioning

confidence: 99%

Loss of parafibromin expression in a subset of parathyroid adenomas

Juhlin¹,

Yakoleva²,

Leibiger³

et al. 2006

Endocr Relat Cancer

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Inactivation of the hyperparathyroidism-jaw tumour syndrome (HPT-JT) gene, HRPT2, was recently established as a genetic mechanism in the development of parathyroid tumours. Its encoded protein parafibromin has tumour-suppressor properties that play an important role in tumour development in the parathyroids, jaws and kidneys. Inactivating HRPT2 mutations are common in HPT-JT and parathyroid carcinomas, and have been described in a few cases of parathyroid adenomas with cystic features. In this study, 46 cases of cystic parathyroid adenomas previously investigated for HRPT2 mutations were characterized with regard to MEN1 gene mutations, cyclin D1 expression and parafibromin expression. In normal tissues and cell lines, parafibromin was ubiquitously expressed. Furthermore, parafibromin was detected as a dominating nuclear and a weaker cytoplasmic signal in transfected cell lines. In the three parathyroid tumours with inactivating HRPT2 mutations parafibromin expression was not detectable, and in one of two cases with aberrantly sized parafibromin the protein was delocalized. Both high and low cyclin D1 levels were found among HRPT2-mutated and -unmutated tumours, suggesting that these events are not mutually exclusive in parathyroid tumour development. The presented data suggest that in the majority of benign parathyroid tumours the expression of parafibromin remains unaltered, while the loss of parafibromin expression is strongly indicative of gene inactivation through mutation of the HRPT2 gene.

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“…Parafibromin is a protein encoded by oncosuppressor gene HRPT2 (hyperparathyroidism 2), whose mutation causes the hyperparathyroidism-jaw tumor syndrome (Aldred et al, 2006). HRPT2 is located in human chromosome 1q31.2, consists of 17 exons, and spans 18.5kb in the genome.…”

Section: Introductionmentioning

confidence: 99%

Effects of Parafibromin Expression on the Phenotypes and Relevant Mechanisms in the DLD-1 Colon Carcinoma Cell Line

Zhao¹,

Sun²,

Zhu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Parafibromin is a protein encoded by the HRPT2 (hyperparathyroidism 2) oncosuppressor gene and its down-regulated expression is involved in pathogenesis of parathyroid, breast, gastric and colorectal carcinomas. This study aimed to clarify the effects of parafibromin expression on the phenotypes and relevant mechanisms of DLD-1 colon carcinoma cells. Methods: DLD-1 cells transfected with a parafibromin-expressing plasmid were subjected to examination of phenotype, including proliferation, differentiation, apoptosis, migration and invasion. Phenotype-related proteins were measured by Western blot. Parafibromin and ki-67 expression was detected by immunohistochemistry on tissue microarrays. Results: The transfectants showed higher proliferation by CCK-8, better differentiation by electron microscopy and ALP activity and more apoptotic resistance to cisplatin by DNA fragmentation than controls. There was no difference in early apoptosis by annexin V, capase-3 activity, migration and invasion between DLD-1 cells and their transfectants. Ectopic parafibromin expression resulted in down-regulated expression of smad4, MEKK, GRP94, GRP78, GSK3β-ser9, and Caspase-9. However, no difference was detectable in caspase-12 and -8 expression. A positive relationship was noted between parafibromin and ki-67 expression in colorectal carcinoma. Conclusions: Parafibromin overexpression could promote cell proliferation, apoptotic resistance, and differentiation of DLD-1 cells.

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Dental findings in a family with hyperparathyroidism–jaw tumor syndrome and a novel HRPT2 gene mutation

Cited by 63 publications

References 21 publications

Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation

Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation

Loss of parafibromin expression in a subset of parathyroid adenomas

Effects of Parafibromin Expression on the Phenotypes and Relevant Mechanisms in the DLD-1 Colon Carcinoma Cell Line

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