Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The syndrome of multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant tumour disease of the neuroendocrine system with manifestations in the parathyroids, pancreas, duodenum and pituitary gland and rarely also in the stomach and thymus. Recently, the MEN 1 gene locus has been mapped to the long arm of chromosome 11. This gene most likely belongs to the tumour suppressor genes, the allelic loss of which causes tumour development. The pancreatic and duodenal tumours may metastasize, but usually have a low malignant potential. Clinically, most MEN 1 patients present between the age of 20 and 35 with hyperparathyroidism and/or Zollinger-Ellison syndrome.
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PMID:[Multiple endocrine neoplasia type 1 (MEN 1). Molecular genetics, morphology and prognosis]. 791 16

Dideoxyfingerprinting was used to screen for germline and somatic MEN1 mutations. This method, applied to a panel of germline DNA from 15 probands with multiple endocrine neoplasia type 1 (MEN-1), allowed confident discovery of the MEN1 gene. Germline MEN1 mutation has been found in 47 out of 50 probands with familial MEN-1, in 7 out of 8 cases with sporadic MEN-1, and in 1 out of 3 cases with atypical sporadic MEN-1. Germline MEN1 mutation was not found in any of five probands with familial hyperparathyroidism. Somatic MEN1 mutations were found in 7 out of 33 parathyroid tumours not associated with MEN-1. Allowing for repeating mutations, a total of 47 different germline or somatic MEN1 mutations have been identified. Most predict inactivation of the encoded 'menin' protein. supporting expectations that MEN1 is a tumour suppressor gene. The 16 observed missense mutations were distributed across the gene, suggesting that many domains are important to its as yet unknown functions.
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PMID:Germline and somatic mutation of the gene for multiple endocrine neoplasia type 1 (MEN1). 968 42

Germ line mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour suppressor gene cause MEN1, a rare familial tumour syndrome associated with parathyroid hyperplasia, adenoma and hyperparathyroidism (HP). Here we investigated the role of the MEN1 gene in isolated sporadic and familial HP. Using RT-PCR single-strand conformational polymorphism screening, somatic (but not germ line) mutations of the MEN1 coding sequence were identified in 6 of 31 (19.3%) adenomas from patients with sporadic primary HP, but none in patients (n=16) with secondary HP due to chronic renal failure. MEN1 mutations were accompanied by a loss of heterozygosity (LOH) for the MEN1 locus on chromosome 11q13 in the adenomas as detected by microsatellite analysis. No DNA sequence divergence within the 5' region of the MEN1 gene, containing the putative MEN1 promoter, was detectable in HP adenomas. Clinical characteristics were not different in HP patients with or without MEN1 mutation. Heterozygous MEN1 gene polymorphisms were identified in 9.6% and 25% of patients with primary and secondary HP respectively. In a large kindred with familial isolated familial HP, MEN1 germ line mutation 249 del4 and LOH was associated with the HP phenotype and a predisposition to non-endocrine malignancies. We suggest that the bi-allelic somatic loss of MEN1 wild-type gene expression is involved in the pathogenesis of a clinically yet undefined subset of sporadic primary HP adenomas. MEN1 genotyping may further help define the familial hyperparathyroidism-MEN1 disease complex, but it seems dispensable in sporadic primary HP.
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PMID:Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region. 1085 77

The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disorder characterized by parathyroid tumours, which are frequently carcinomas, and ossifying jaw fibromas. In addition, some patients may develop renal tumours and cysts. The gene causing HPT-JT, which is referred to as HRPT2 and is located on chromosome 1q31.2, encodes a 531 amino acid protein called PARAFIBROMIN. To date 42 mutations, of which 22 are germline, have been reported and 97% of these are inactivating and consistent with a tumour suppressor role for HRPT2. We have investigated another four HPT-JT families for germline mutations, searched for additional clinical phenotypes, and examined for a genotype-phenotype correlation. Mutations were found in two families. One family had a novel deletional-insertion at codon 669, and the other had a 2 bp insertion at codon 679, which has been reported in four other unrelated patients. These five unrelated patients and their families with the same mutation were not found to develop the same tumours, thereby indicating an absence of a genotype-phenotype correlation. An analysis of 33 HPT-JT kindreds revealed that affected women in 13 HPT-JT families suffered from menorrhagia in their second to fourth decades. This often required hysterectomy, which revealed the presence of uterine tumours. This resulted in a significantly reduced maternal transmission of the disease. Thus, the results of our analysis expand the spectrum of HPT-JT-associated tumours to include uterine tumours, and these may account for the decreased reproductive fitness in females from HPT-JT families.
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PMID:Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. 1560 73

Individuals with inherited cancer syndromes are at significant risk of developing both benign and malignant tumours as a result of a germline mutation in a specific tumour suppressor gene. Tumours of familial origin are a rare event in the head and neck but despite this, they deserve a growing interest. Familial paragangliomas are most of the time limited to the paraganglionar system, but also may be part of different syndromic associations. Since early detection of paragangliomas reduces the incidence of morbidity and mortality, genotypic analysis in the search of SDHB, SDHC and SDHD mutations in families of affected patients plays a front-line diagnostic role, leading to more efficient patient management. Multiple endocrine neoplasias type 1 are characterized by the simultaneous occurrence of at least two of the three main related endocrine tumours: parathyroid, enteropancreatic and anterior pituitary. These tumours arise from inactivating germline mutations in the MEN-1 gene. No clear correlation of MEN-1 genotype with genotype has emerged to date, and MEN-1 mutation testing in tumours is not used clinically because it have not implications for tumour staging. Multiple endocrine neoplasia type 2 is due to a germline mutation in the RET proto-oncogene. Hallmarks of MEN-2A (the commonest phenotypic variant) include medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. The most central clinical difference with MEN-1 is that the associated cancer can be prevented or cured by early thyroidectomy in mutation carriers. Individuals with neurofibomatosis type 1 present early in life with pigmentary abnormalities, skinfold freckling and iris hamartomas, as result of NF1 gene mutation. Neurofibromatosis 2 is caused by inactivating mutations of the NF2 gene, and is characterized by the development of nervous system tumours (mainly bilateral vestibular schwannomas), ocular abnormalities, and skin tumours. The molecular genetic basis of nasopharyngeal carcinomas remains unknown, but there is evidence for the linkage of these tumours to chromosome 3p. Finally, the high rate of p16 mutations in squamous cell carcinomas and the association of p16 with familial melanoma propose p16 as an ideal candidate gene predisposing to familial squamous cell carcinomas. The elucidation of the cellular processes affected by dysfunction in familial tumours of the head and neck may serve to identify potential targets for future therapeutic interventions.
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PMID:Tumours of familial origin in the head and neck. 1685 15

Parafibromin is a nuclear protein with a tumour suppressor role in the development of non-hereditary and hereditary parathyroid carcinomas, and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome, which is associated with renal and uterine tumours. Nuclear localization signal(s), (NLS(s)), of the 61 kDa parafibromin remain to be defined. Utilization of computer-prediction programmes, identified five NLSs (three bipartite (BP) and two monopartite (MP)). To investigate their functionality, wild-type (WT) and mutant parafibromin constructs tagged with enhanced green fluorescent protein or cMyc were transiently expressed in COS-7 cells, or human embryonic kidney 293 (HEK293) cells, and their subcellular locations determined by confocal fluorescence microscopy. Western blot analyses of nuclear and cytoplasmic fractions from the transfected cells were also performed. WT parafibromin localized to the nucleus and deletions or mutations of the three predicted BP and one of the predicted MP NLSs did not affect this localization. In contrast, deletions or mutations of a MP NLS, at residues 136-139, resulted in loss of nuclear localization. Furthermore, the critical basic residues, KKXR, of this MP NLS were found to be evolutionarily conserved, and over 60% of all parafibromin mutations lead to a loss of this NLS. Thus, an important functional domain of parafibromin, consisting of an evolutionarily conserved MP NLS, has been identified.
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PMID:Parafibromin is a nuclear protein with a functional monopartite nuclear localization signal. 1696 91

Hyperparathyroidism-jaw tumour (HPT-JT) syndrome is characterized by parathyroid tumours as well as by ossifying fibromas of the mandible and maxilla, renal cysts, or Wilms' tumours. Recently, the gene responsible for HPT-JT syndrome has been identified as the HRPT2 tumour suppressor gene. In an 18-year-old male, a tumour in the maxilla was first diagnosed as an ossifying fibroma. During biochemical screening before surgery, the patient received a diagnosis of primary hyperparathyroidism. Neck computed tomography scanning showed a parathyroid tumour. Surgical excisions to remove the jaw tumour and parathyroid adenoma were performed. The postoperative course has been uneventful and a follow up at 2 years revealed no evidence of recurrence. The HRPT2 germline mutation of 39delC was detected in the proband, but not in his unaffected parents. These results suggested that the germline mutation occurred de novo.
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PMID:A case of hyperparathyroidism-jaw tumour syndrome found in the treatment of an ossifying fibroma in the maxillary bone. 1705 94

Parathyroid carcinoma (PC) is an uncommon finding, accounting for only 1-2% of patients with primary hyperparathyroidism (HPT), but a relatively higher incidence has been reported in Italy and Japan. The etiology of the tumour remains unclear, but molecular analysis studies have hypothesised the involvement of mutations of several genes in the pathogenesis of PC, including the oncogene cyclin Dl or PRADI located at the chromosome 13, the retinoblastoma and the p53 tumour suppressor gene. The clinical presentation of patients with PC is mainly related to the increased secretion of PTH rather than to the tumour burden. The pre-operative diagnosis of malignancy is very difficult to obtain, and, thus, intra-operative recognition of PC is mandatory. However, reliable signs of malignancy are rarely detectable. Probably, only vascular invasion, that correlates with tumour recurrence and metastases, should be considered useful in confirming malignancy, although both Ki-67 and Cyclin D1 have been recently used to aid in the definitive diagnosis. The en bloc resection of the tumour, together with ipsilateral thyroid lobe and adjacent structures, only if involved, avoiding any capsular rupture of the mass, represents the gold standard of surgical treatment of patients. Although the PC has traditionally been considered as a radioresistant tumour, there are some retrospective data holding a possible benefit from post-operative irradiation. No cytotoxic regimen with proven efficacy is currently available for patients with PC, but since hypercalcemia is ultimately the most frequent cause of death, several studies have suggested the usefulness of bisphosphonates (i.e., clodronate, pamidronate and zoledronate), calcitonin, and calcimimetic agents (i.e., cinacalcet) in patients with PC and severe hypercalcemia. In conclusion, PC is a rare malignancy and the NCDB survey reports an overall five- and ten-year survival rate of 85% and 49%, respectively. However, it is very difficult to predict the clinical behaviour of patients with PC and probably the ultimate prognosis depends on successful resection of the tumour at the initial surgery.
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PMID:Parathyroid cancer: etiology, clinical presentation and treatment. 1721 44

Multiple endocrine neoplasia (MEN) are major predisposition syndromes to endocrine tumours and are characterised by an autosomal dominant disorder and full penetrance. MEN-1 is a major form of hyperparathyroidism associated with a high prevalence of endocrine tumours of the pancreas, pituitary gland, adrenal cortex and the lymphoid and bronchial endocrine tissues. MEN-2 is the familial syndrome of medullary thyroid carcinoma, associated with pheochromocytoma and hyperparathyroidism. Apart from the clinical expression of their allelic variants, both syndromes are different in their physiopathogenesis, in that MEN-2 is related to the constitutional activation of the proto-oncogene RET that encodes a putative tyrosine kinase receptor, while MEN-1 is a tumour suppressor gene model, related to mutations in the menin adapter-protein of multiple intracellular functions. The study of other rarer forms of predisposition to endocrine tumours, and especially to hyperparathyroidism, has uncovered new genes such as HRPT2, which show that multiple physiological routes, including the close regulation of transcription and genetic stability, may lead to the same clinical outcome. These hereditary models of endocrine cancer contribute as much to further physiopathogenic knowledge as to the therapeutic recommendations for managing these syndromes.
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PMID:[Pathogenic patterns of genetic predisposition to endocrine tumors]. 1737 13

Mutations in the tumour suppressor HRPT2 occur in patients with parathyroid carcinoma, kidney tumours and Hyperparathyroidism-Jaw Tumour syndrome. Disruption of exonic splicing through mutation of donor/acceptor splice sites or exonic splice enhancer (ESE) sites leads to loss of function of a number of major tumour suppressors including BRCA1, APC and MLH1. Given that the effect of HRPT2 mutations on splicing has not been widely studied, we used an in vitro splicing assay to determine whether 17 HRPT2 mutations located in hot-spot and other exons predicted to disrupt ESE consensus sites led to aberrant splicing. Using two independent web-based prediction programs, the majority of these mutations were predicted to disrupt ESE consensus sites; however, aberrant splicing of HRPT2 transcripts was not observed. Canonical donor or acceptor splice site mutations were also investigated using this splicing assay and transcripts assessed from tumour tissue. Splice site mutations were shown to lead to either exon skipping or retention of intronic sequences through the use of cryptic splice sites comprised of non-classical splicing signals. Aberrant splicing caused by disruption of ESE sites does not appear to have a major role in HRPT2-associated disease; however, premature truncation of parafibromin as the result of canonical donor or acceptor splice site mutations is associated with pathogenicity. Functional splicing assays must be undertaken in order to confirm web-based software predictions of the modification of putative ESE sites by disease-associated mutations.
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PMID:The effect of disease-associated HRPT2 mutations on splicing. 1933 51


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