| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
IRCCS-IOV (Istituto Oncologico Veneto), I-35128 Padova, Italy1 Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, Via A. Gabelli 63, I-35121 Padova, Italy2 Endocrine Surgery Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, I-35128 Padova, Italy3 Department of Human Anatomy and Physiology, University of Padova, I-35121 Padova, Italy
(Correspondence should be addressed to L Barzon; Email: luisa.barzon{at}unipd.it)
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and methodsResultsDiscussionDeclaration of interestReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and methodsResultsDiscussionDeclaration of interestReferences |
|---|
Germline mutations in CDC73 have been identified not only in about 60% of HPT-JT kindreds (Carpten et al. 2002) and in one-third of patients with apparently sporadic parathyroid carcinoma (Howell et al. 2003, Shattuck et al. 2003, Cetani et al. 2004), but also in 7% of kindreds with familial isolated HPT (FIHP; OMIM#145000; Simonds et al. 2004, Villablanca et al. 2004, Bradley et al. 2006, Mizusawa et al. 2006), a heterogeneous disease, which has also been related to MEN1 and CASR mutations (Hannan et al. 2008). Germline and somatic mutations identified so far are scattered throughout the coding region of the CDC73 gene and most are predicted to result in truncated or inactive forms of parafibromin (Carpten et al. 2002, Villablanca et al. 2004). Parafibromin inactivation has been confirmed by immunohistochemical and functional studies, which demonstrated that CDC73 mutations result in the loss of parafibromin expression (Tan et al. 2004, Gill et al. 2006, Juhlin et al. 2006) or abnormal subcellular localization (Bradley et al. 2007, Lin et al. 2007) and abolition of its anti-proliferative activity (Zhang et al. 2006), even though experiments with knockout mice indicate that expression of parafibromin is pivotal in mammalian development and survival in adults, whereas its loss leads to apoptosis in vitro (Wang et al. 2008).
This study reports the results of clinical, genetic, and histopathologic investigation of three unrelated Italian kindreds with HPT-JT and FIHP. The presence of germline and somatic CDC73 mutations in all kindreds, the occurrence of tumors other than parathyroid, and the loss of parafibromin expression in parathyroid and uterine tumors suggested that HPT-JT and FIHP could be variants of the same genetic disease.
|
Subjects and methods |
|---|
|
TopAbstractIntroductionSubjects and methodsResultsDiscussionDeclaration of interestReferences |
|---|
The study population consists in a large HPT-JT kindred, including 6 clinically symptomatic and 9 asymptomatic subjects, and 2 unrelated FIHP kindreds, including a total of 10 symptomatic and 13 asymptomatic subjects (Fig. 1), which were evaluated at the Endocrine Surgery Department of the University of Padua and previously published in part (Iacobone et al. 2007). Informed consent for the collection of personal, genetic, and clinical data was obtained from all patients and the study was approved by the local ethics committee.
|
In- and outpatient medical records were reviewed for clinical and biochemical details; complete follow-up data were obtained by extensive clinical and laboratory reevaluation or personal telephone interview designed to elicit all information regarding the patient's current state of health, the most recent laboratory determinations, and the presence of other eventually affected relatives.
Screening for MEN1- and MEN2-associated tumors included laboratory and imaging evaluation of the pancreas, pituitary, adrenals, and thyroid C cells component.
Complete bilateral neck exploration and selective parathyroidectomy of the macroscopically abnormal glands and biopsy of the normal appearing parathyroids were performed as reported (Iacobone et al. 2007).
Screening for jaw tumors used orthopantographic X-rays and/or CT of the mandible and maxilla. Evaluation of the kidneys used standard ultrasound, abdominal MRI or CT scan. Uterine abnormalities were assessed by standard ultrasound and/or hysteroscopic examination and eventually confirmed at biopsy.
Tissue samples and pathological investigation
Parathyroid specimens were carefully reviewed, and the diagnosis confirmed according to the World Health Organization guidelines (DeLellis et al. 2004). Frozen and paraffin-embedded specimens from four parathyroid adenomas (patients II-2 and II-3, HPT-JT kindred; patient IV-3, FIHP kindred 1; patient IV-1, FIHP kindred 2) and three normal parathyroid glands (patients II-2 and II-3, HPT-JT kindred; patient IV-1, FIHP kindred 2) were available for genetic and immunohistochemical studies. Other three paraffin-embedded parathyroid adenomas (patient III-2, HPT-JT kindred; patient IV-4, FIHP kindred 1; patient III-1, FIHP kindred 2), a parathyroid carcinoma (patient I-1, HPT-JT kindred), and tissues from multiple endometrial hyperplastic polyps from patient II-3 of the HPT-JT kindred were available for immunohistochemistry. Ten normal parathyroids, which were accidentally removed at the time of thyroid surgery for benign diseases from patients without clinical and biochemical evidence of HPT, and five sporadic endometrial hyperplastic polyps from age-matched patients without germline CDC73 mutations were taken as control groups.
Mutation analysis of the CDC73 gene
Genomic DNA was isolated from peripheral blood leukocytes of probands and available family members and from parathyroid frozen tissues using a QIA Amp DNA Mini Kit (Qiagen GmbH). The entire coding region and the intron–exon boundaries of the CDC73 gene were sequenced by PCR amplification using oligonucleotide primer sequences previously reported (Shattuck et al. 2003) and bidirectional sequencing of PCR products using an ABI PRISM BigDye terminators v3.1 cycle sequencing kit (Applied Biosystems, Foster City, CA, USA). Sequences were run on an Applied Biosystems 3130 Genetic Analyzer (Applied Biosystems) and compared with the reference sequence Gene ID 79577. All genetic alterations were confirmed by a second independent sequencing reaction performed on a second blood sample. Moreover, in order to better define heterozygous frameshift mutations, PCR amplicons carrying the mutations were subcloned into pGEM-T Easy vectors (Promega, Madison, WI, USA) to separate the two alleles and resequenced as above described.
Methylation analysis of the CDC73 promoter
The methylation status of the CDC73 promoter region including 65 CpG sites was assessed by bisulfite sequencing. To this aim, genomic DNA from leukocytes and tumor tissues was modified by bisulfite treatment and subsequently purified using an EpiTect Bisulfite Kit (Qiagen GmbH) according to the manufacturer's recommendations. Bisulfite-treated DNA was amplified with primers from Mizusawa et al. (2006) and PCR products were cloned into a pGEM-T Easy vector. Five clones were each sequenced as above described. Sequences from parathyroid tumors and corresponding leukocytes were compared.
Immunohistochemistry
Parafibromin expression was evaluated by immunohistochemical staining on a parathyroid carcinoma, seven parathyroid adenomas, and three normal parathyroids surgically removed from HPT-JT and FIHP patients, and on endometrial hyperplastic polyps from the HPT-JT patient. Anti-parafibromin immunohistochemistry was also performed on control normal parathyroids and sporadic endometrial hyperplastic polyps. Immunohistochemistry was performed on formalin-fixed and paraffin-embedded tissues as previously described (Porzionato et al. 2006), using a mouse monoclonal anti-parafibromin antibody (SC-33638, Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA) raised to target amino acids 87–100 of parafibromin. Slide sections were examined by scanning the entire tissue specimens under low power magnification (5–10x), later confirmed at higher power magnification (20–40x).
Statistical analysis
Demographics, clinical, and laboratory features of HPT-JT and FIHP kindreds were compared by Fisher's exact test and Mann–Whitney test. A P<0.05 was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and methodsResultsDiscussionDeclaration of interestReferences |
|---|
Clinical features of investigated subjects are summarized in Table 1. Laboratory and imaging evaluation of pancreas, pituitary, thyroid C cells, and adrenals did not show any abnormalities in all screened patients. In all patients, a single-gland parathyroid involvement was found at each surgical procedure.
|
FIHP kindred 1
The proband (IV-3) had parathyroid adenoma and uterine polyposis. Her sister (IV-4) had recurrent HPT due to parathyroid adenomas, uterine polyposis, and thyroid adenoma (Fig. 1B). The other effected family members (III-4, III-8) had parathyroid adenoma. Subjects II-3 and IV-2 had parathyroid adenomas and underwent surgery elsewhere; subject II-3 had also uterine involvement. Subjects III-5, IV-13, and V-2 (aged 60, 15, and 13 years) are unaffected carriers of germline CDC73 mutations. No renal or jaw tumors were detected in this kindred.
FIHP kindred 2
The proband (III-1) had parathyroid adenoma, which was operated on at 38 years, and multiple uterine polyposis (Fig. 1C). Her daughter (IV-1) underwent surgery for parathyroid adenoma at 23 years. Patient III-5 underwent excision of a single parathyroid adenoma elsewhere at the age of 38 years; she had also uterine involvement. Patient II-4 had a biochemical diagnosis of HPT, but refused surgery. Patient II-1 died at 67 years because of renal carcinoma. To date, no jaw tumors have been detected in this kindred.
No significant differences were found between HPT-JT and FIHP kindreds according to the occurrence of primary HPT (63 vs 67% respectively, in subjects carrying CDC73 mutations), age at diagnosis of HPT (median, 25.5 years; range, 11–56 years vs 38 years; range, 23–71 respectively), total serum calcium levels (mean, 3.2±0.7 mmol/l vs 3.2±0.4 mmol/l), and plasma parathyroid hormone (PTH) levels (mean, 269±388 pg/ml vs 166±75 pg/ml).
CDC73 mutation and methylation analysis
The proband of HPT-JT kindred (II-2) carried a previously unreported germline heterozygous frameshift mutation in exon 6 of the CDC73 gene (c.433_442delinsAGA), which predicts an alteration of the reading frame with a premature truncation at codon 201 (Fig. 2A). Genetic testing was extended to 13 members of the kindred, and the CDC73 mutation was detected in other 4 affected and 3 unaffected family members (Fig. 1A). Both normal and mutant alleles were retained in the two investigated parathyroid tumors and no additional somatic CDC73 mutations were identified.
|
In FIHP kindred 2, a germline heterozygous five-nucleotides deletion c.(136_144)del5 in exon 2 was detected in the index case patient (III-1) and in her daughter (Fig. 2D), while it was not detected in the healthy subjects IV-2 and V-1. The mutation determines a frameshifting that leads to formation of a stop codon at residue 62. Heterozygosity of the mutation was retained in an investigated parathyroid adenoma (IV-1).
Methylation analysis of the CDC73 promoter in the DNA purified from two parathyroid adenomas without somatic CDC73 mutations, obtained from two patients (II-2; II-3) of HPT-JT kindred 1 and in the corresponding leukocytes did not demonstrate any methylated CpG site.
Analysis of parafibromin expression
Anti-parafibromin nuclear immunostaining was absent in almost all tumor cells in the parathyroid carcinoma and in all parathyroid adenomas from HPT-JT and FIHP patients. At variance, intense nuclear immunostaining (>90% of parathyroid cells) was present in all normal parathyroids obtained at surgery from both HPT-JT and FIHP patients and controls (Fig. 3). In the HPT-JT-related uterine polyp, stromal cells did not show any anti-parafibromin nucleocytoplasmatic reactivity, whereas epithelial cells had no nuclear immunostaining but moderate cytoplasmic immunoreactivity. In the five sporadic uterine polyps from the control group, stromal cells showed positive nuclear anti-parafibromin immunostaining and epithelial cells showed intense nuclear immunostatining and moderate cytoplasmic positivity (Fig. 4).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and methodsResultsDiscussionDeclaration of interestReferences |
|---|
The results of our study confirm the idea that HPT-JT and FIHP (when associated with CDC73 mutations) may be variants of the same disease, since our kindreds, besides sharing the same genetic background, characterized by germline inactivating mutations of the CDC73 gene, had also similar clinical features. In fact, the age of onset of HPT and laboratory data were not significantly different in FIHP and HPT-JT patients, even though parathyroid carcinoma and atypical adenoma were found exclusively in the HPT-JT kindred. On the other hand, a revision of the literature shows that parathyroid carcinoma occurs quite frequently also in FIHP kindreds (Carpten et al. 2002, Bradley et al. 2005b). Furthermore, other typical clinical features, such as uterine polyposis and other neoplasms, were present in both HPT-JT and FIHP kindreds, in agreement with the literature (Carpten et al. 2002, Bradley et al. 2005b). Besides primary HPT, which was diagnosed in 63% HPT-JT patients and in 67% FIHP patients carrying CDC73 mutations, uterine polyposis was the second most common clinical feature in our patients, being identified in 75% of affected HPT-JT female patients and 56% of FIHP female patients, as also reported in the literature (Cavaco et al. 2004, Bradley et al. 2005b, Guarnieri et al. 2006).
Other neoplastic lesions were less frequent. Only one out of six affected members of the HPT-JT kindred had a jaw tumor. Variable penetrance of this syndromic feature has been reported in the literature (Carpten et al. 2002, Cavaco et al. 2004, Bradley et al. 2005b). As previously reported (Haven et al. 2000, Carpten et al. 2002, Cavaco et al. 2004, Bradley et al. 2005b), we also identified two cases of papillary thyroid carcinoma in HPT-JT patients, even though the exclusive finding of microscopic foci at a preclinical stage might be considered an occasional finding during targeted neck investigation rather than a clinical feature of the syndromes. Cystic or neoplastic renal involvement has been reported in 0–70% of CDC73 mutation carriers (Carpten et al. 2002, Howell et al. 2003, Cavaco et al. 2004, Villablanca et al. 2004, Bradley et al. 2005b, Guarnieri et al. 2006); in this regard, we identified only one case of kidney cancer in a patient without HPT from a FIHP kindred. However, the CDC73 mutation status of this patient is unknown, so we cannot exclude the renal cancer may be unrelated to the syndrome. Finally, we found a locally advanced colon carcinoma in a relatively young HPT-JT patient, an unusual finding in HPT-JT (Simonds et al. 2002). Unfortunately, a tumor sample was not available for genetic testing and parafibromin immunostaining, so, even in this case, the association between occurrence of colon cancer and CDC73 mutation cannot be established.
Genetic investigation demonstrated that both HPT-JT and FIHP kindreds carried germline mutations of the CDC73 gene. Mutations were predicted to result in truncated or inactive parafibromin, in agreement with its tumor suppressor activity. In addition, somatic CDC73 mutations and/or loss of parafibromin expression were detected in parathyroid tumors from both HPT-JT and FIHP patients. Three of the CDC73 mutations we identified have never been reported before in the literature, i.e., c.433_442delinsAGA germline mutation (the first mutation reported to date at exon 6), c.375_376insAA, and the germline Leu63Pro missense mutation. The fourth mutation, i.e., the germline five-nucleotides deletion c.(136_144)del5 identified in FIHP kindred 2, has been previously described by Kelly et al. 2006 as c.140_144del5 in an Australian kindred with FIHP. While the three frameshifting mutations are predicted to result in truncated forms of parafibromin, the Leu63Pro germline missense mutation changes a conserved leucine at codon 63 with proline. A similar mutation in the adjacent codon, Leu64Pro, has been already reported in FIHP kindreds (Howell et al. 2003, Villablanca et al. 2004). This mutation, characterized by a substitution of the hydrophobic amino acid leucine with the helix breaker amino acid proline, might cause a significant alteration in the structure of parafibromin and impair its activity, as demonstrated in in vitro experiments (Woodard et al. 2005).
CDC73 mutations reported so far in the literature (Table 2) are scattered along the sequence of the gene, with a higher number of mutations in exons 1–2 and 7–8, but no mutations in exons 9–12 and 14–17. Germline frameshift and nonsense CDC73 mutations are the most frequent mutations, representing 88 and 57% of the mutations identified in HPT-JT and FIHP kindreds respectively, whereas germline missense mutations are rather infrequent and generally affect functionally important regions of parafibromin. No genotype–phenotype correlation has been identified so far.
|
In the literature, association of uterine tumors with the HPT-JT syndrome has been reported (Fujikawa et al. 1998, Bradley et al. 2005b). Our study supports this association and, to the best of our knowledge, is the first one which compares parafibromin expression in HPT-JT-related polyps with sporadic ones. The loss of parafibromin nuclear immunostaining in both stromal and epithelial components of HPT-JT polyps, with respect to sporadic ones, supports the pathogenetic role for CDC73 mutations in uterine polyposis associated with this syndrome.
In conclusion, our results indicate that FIHP and HPT-JT associated with CDC73 mutations do not have distinct genetic, clinical, and pathological features, but may represent variants of the same genetic disease, which could be defined CDC73-related familial HPT. Penetrance of mutations is high, but disease expression may be incomplete. The most common clinical presentation is primary HPT, that may occur very early, but other tumors are also frequently diagnosed, such as uterine polyposis.
|
Declaration of interest |
|---|
|
TopAbstractIntroductionSubjects and methodsResultsDiscussionDeclaration of interestReferences |
|---|
|
Funding |
|---|
|
Acknowledgements |
|---|
|
References |
|---|
|
TopAbstractIntroductionSubjects and methodsResultsDiscussionDeclaration of interestReferences |
|---|
Bradley KJ, Cavaco BM, Bowl MR, Harding B, Young A & Thakker RV 2005a Utilisation of a cryptic non-canonical donor splice site of the gene encoding PARAFIBROMIN is associated with familial isolated primary hyperparathyroidism. Journal of Medical Genetics 42 e51
Bradley KJ, Hobbs MR, Buley ID, Carpten JD, Cavaco BM, Fares JE, Laidler P, Manek S, Robbins CM, Salti IS et al. 2005b Uterine tumours are a phenotypic manifestation of the hyperparathyroidism–jaw tumour syndrome. Journal of Internal Medicine 257 18–26.[CrossRef][Web of Science][Medline]
Bradley KJ, Cavaco BM, Bowl MR, Harding B, Cranston T, Fratter C, Besser GM, Conceicao Pereira M, Davie MW, Dudley N et al. 2006 Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours. Clinical Endocrinology 64 299–306.[CrossRef][Medline]
Bradley KJ, Bowl MR, Williams SE, Ahmad BN, Partridge CJ, Patmanidi AL, Kennedy AM, Loh NY & Thakker RV 2007 Parafibromin is a nuclear protein with a functional monopartite nuclear localization signal. Oncogene 26 1213–1221.[CrossRef][Web of Science][Medline]
Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD et al. 2002 HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome. Nature Genetics 32 676–680.[CrossRef][Web of Science][Medline]
Cavaco BM, Guerra L, Bradley KJ, Carvalho D, Harding B, Oliveira A, Santos MA, Sobrinho LG, Thakker RV & Leite V 2004 Hyperparathyroidism–jaw tumor syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene. Journal of Clinical Endocrinology and Metabolism 89 1747–1752.
Cetani F, Pardi E, Borsari S, Viacava P, Dipollina G, Cianferotti L, Ambrogini E, Gazzerro E, Colussi G, Berti P et al. 2004 Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. Journal of Clinical Endocrinology and Metabolism 89 5583–5591.
Cetani F, Ambrogini E, Viacava P, Pardi E, Fanelli G, Naccarato AG, Borsari S, Lemmi M, Berti P, Miccoli P et al. 2007a Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma? European Journal of Endocrinology 156 547–554.
Cetani F, Pardi E, Ambrogini E, Viacava P, Borsari S, Lemmi M, Cianferotti L, Miccoli P, Pinchera A, Arnold A et al. 2007b Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation. Endocrine-Related Cancer 14 493–499.
DeLellis RA, Lloyd RV, Heitz PU & Heng C World Health Organization Classification of Tumours Pathology and Genetics: Tumours of Endocrine Organs. 2004IARC PressLyon, France:
Fujikawa M, Okamura K, Sato K, Mizokami T, Tamaki K, Yanagida T & Fujishima M 1998 Familial isolated hyperparathyroidism due to multiple adenomas associated with ossifying jaw fibroma and multiple uterine adenomyomatous polyps. European Journal of Endocrinology 138 557–561.[Abstract]
Gill AJ, Clarkson A, Gimm O, Keil J, Dralle H, Howell VM & Marsh DJ 2006 Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism–jaw tumor (HPT-JT) syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias. American Journal of Surgical Pathology 30 1140–1149.[Web of Science][Medline]
Guarnieri V, Scillitani A, Muscarella LA, Battista C, Bonfitto N, Bisceglia M, Minisola S, Mascia ML, D'Agruma L & Cole DE 2006 Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: implications for cancer surveillance. Journal of Clinical Endocrinology and Metabolism 91 2827–2832.
Hannan FM, Nesbit MA, Christie PT, Fratter C, Dudley NE, Sadler GP & Thakker RV 2008 Familial isolated primary hyperparathyroidism caused by mutations of the MEN1 gene. Nature Clinical Practice. Endocrinology & Metabolism 4 53–58.[Web of Science][Medline]
Haven CJ, Wong FK, van Dam EW, van der Juijt R, van Asperen C, Jansen J, Rosenberg C, de Wit M, Roijers J, Hoppener J et al. 2000 A genotypic and histopathological study of a large Dutch kindred with hyperparathyroidism–jaw tumor syndrome. Journal of Clinical Endocrinology and Metabolism 85 1449–1454.
Haven CJ, van Puijenbroek M, Tan MH, Teh BT, Fleuren GJ, van Wezel T & Morreau H 2007 Identification of MEN1 and HRPT2 somatic mutations in paraffin-embedded (sporadic) parathyroid carcinomas. Clinical Endocrinology 67 370–376.[Medline]
Howell VM, Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, Fleuren GJ, Robinson BG, Delbridge LW, Philips J et al. 2003 HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. Journal of Medical Genetics 40 657–663.
Iacobone M, Barzon L, Porzionato A, Masi G, Macchi V, Marino F, Viel G & Favia G 2007 Parafibromin expression, single-gland involvement and limited parathyroidectomy in familial isolated hyperparathyroidism. Surgery 142 984–991.[Medline]
Jackson CE, Norum RA, Boyd SB, Talpos GB, Wilson SD, Taggart RT & Mallette LE 1990 Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome. Surgery 108 1006–1012.[Web of Science][Medline]
Juhlin C, Larsson C, Yakoleva T, Leibiger I, Leibiger B, Alimov A, Weber G, Höög A & Villablanca A 2006 Loss of parafibromin expression in a subset of parathyroid adenomas. Endocrine-Related Cancer 13 509–523.
Juhlin CC, Villablanca A, Sandelin K, Haglund F, Nordenstrom J, Forsberg L, Branstrom R, Obara T, Arnold A, Larsson C et al. 2007 Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification. Endocrine-Related Cancer 14 501–512.
Kelly TG, Shattuck TM, Reyes-Mugica M, Stewart AF, Simonds WF, Udelsman R, Arnold A & Carpenter TO 2006 Surveillance for early detection of aggressive parathyroid disease: carcinoma and atypical adenoma in familial isolated hyperparathyroidism associated with a germline HRPT2 mutation. Journal of Bone and Mineral Research 21 1666–1671.[CrossRef][Web of Science][Medline]
Lin L, Czapiga M, Nini L, Zhang JH & Simonds WF 2007 Nuclear localization of the parafibromin tumor suppressor protein implicated in the hyperparathyroidism–jaw tumor syndrome enhances its proapoptotic function. Molecular Cancer Research 5 183–193.
Mizusawa N, Uchino S, Iwata T, Tsuyuguchi M, Suzuki Y, Mizukoshi T, Yamashita Y, Sakurai A, Suzuki S, Beniko M et al. 2006 Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism–jaw tumour syndrome. Clinical Endocrinology 65 9–16.[CrossRef][Medline]
Moon SD, Park JH, Kim EM, Kim JH, Han JH, Yoo SJ, Yoon KH, Kang MI, Lee KW, Son HY et al. 2005 Novel IVS2-1G>A mutation causes aberrant splicing of the HRPT2 gene in a family with hyperparathyroidism–jaw tumor syndrome. Journal of Clinical Endocrinology and Metabolism 90 878–883.
Mosimann C, Hausmann G & Basler K 2006 Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo. Cell 125 327–341.[CrossRef][Web of Science][Medline]
Pimenta FJ, Gontijo Silveira LF, Tavares GC, Silva AC, Perdigão PF, Castro WH, Gomez MV, Teh BT, De Marco L & Gomez RS 2006 HRPT2 gene alterations in ossifying fibroma of the jaws. Oral Oncology 42 735–739.[Medline]
Porzionato A, Macchi V, Barzon L, Masi G, Iacobone M, Parenti A, Palù G & De Caro R 2006 Immunohistochemical assessment of parafibromin in mouse and human tissues. Journal of Anatomy 209 817–827.[CrossRef][Medline]
Sarquis MS, Silveira LG, Pimenta FJ, Dias EP, Teh BT, Friedman E, Gomez RS, Tavares GC, Eng C & De Marco L 2008 Familial hyperparathyroidism: surgical outcome after 30 years of follow-up in three families with germline HRPT2 mutations. Surgery 143 630–640.[Medline]
Shattuck TM, Välimäki S, Obara T, Gaz RD, Clark OH, Shoback D, Wierman ME, Tojo K, Robbins CM, Carpten JD et al. 2003 Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. New England Journal of Medicine 349 1722–1729.
Simonds WF, James-Newton LA, Agarwal SK, Yang B, Skarulis MC, Hendy GN & Marx SJ 2002 Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine 81 1–26.[CrossRef][Medline]
Simonds WF, Robbins CM, Agarwal SK, Hendy GN, Carpten JD & Marx SJ 2004 Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism–jaw tumor syndrome. Journal of Clinical Endocrinology and Metabolism 89 96–102.
Tan MH, Morrison C, Wang P, Yang X, Haven CJ, Zhang C, Zhao P, Tretiakova MS, Korpi-Hyovalti E, Burgess JR et al. 2004 Loss of parafibromin immunoreactivity is a distinguishing feature of parathyroid carcinoma. Clinical Cancer Research 10 6629–6637.
Villablanca A, Calender A, Forsberg L, Höög A, Cheng JD, Petillo D, Bauters C, Kahnoski K, Ebeling T, Salmela P et al. 2004 Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP). Journal of Medical Genetics 41 e32
Wang P, Bowl MR, Bender S, Peng J, Farber L, Chen J, Ali A, Alberts AS, Thakker RV, Shilatifard A et al. 2008 Parafibromin, a component of the human PAF complex, regulates growth factors and is required for embryonic development and survival in adult mice. Molecular and Cellular Biology 28 2930–2940.
Woodard GE, Lin L, Zhang JH, Agarwal SK, Marx SJ & Simonds WF 2005 Parafibromin, product of the hyperparathyroidism–jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression. Oncogene 24 1272–1276.[CrossRef][Web of Science][Medline]
Yart A, Gstaiger M, Wirbelauer C, Pecnik M, Anastasiou D, Hess D & Krek W 2005 The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II. Molecular and Cellular Biology 25 5052–5060.
Zhang C, Kong D, Tan MH, Pappas DL Jr, Wang PF, Chen J, Farber L, Zhang N, Koo HM, Weinreich M et al. 2006 Parafibromin inhibits cancer cell growth and causes G1 phase arrest. Biochemical and Biophysical Research Communications 350 17–24.[CrossRef][Web of Science][Medline]
Zhao J, Yart A, Frigerio S, Perren A, Schraml P, Weisstanner C, Stallmach T, Krek W & Moch H 2007 Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene. Oncogene 26 3440–3449.[CrossRef][Web of Science][Medline]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
