Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Medullary thyroid carcinoma (MTC) occurs as a component of three well-described autosomal dominant familial cancer syndromes. Multiple endocrine neoplasia type 2A (MEN 2A) is characterized by MTC, pheochromocytomas, and parathyroid hyperplasia. Patients with the rarer multiple endocrine neoplasia type 2B (MEN 2B) syndrome develop MTC and pheochromocytomas, as well as mucosal neuromas, ganglioneuromatosis of the gastrointestinal tract, and a characteristic "marfanoid" habitus. Finally, MTC is transmitted in an autosomal dominant pattern in some families without associated pheochromocytomas or parathyroid hyperplasia (familial medullary thyroid carcinoma, MTC1(2). Sixty-one members of two well-characterized kindreds segregating MTC1 and 34 [corrected] members of six families segregating MEN2B were genotyped using a panel of RFLP probes from the pericentromeric region of chromosome 10 near a locus for MEN 2A. Statistically significant linkage was observed between the chromosome 10 centromere-specific marker D10Z1 and MTC1 (maximum pairwise lod score 5.88 with 0% recombination) and D10Z1 and MEN2B (maximum pairwise lod score 3.58 with 0% recombination). A maximum multipoint lod score of 4.08 was obtained for MEN2B at the position of D10Z1. In addition, 92 members of a previously unreported large MEN2A kindred were genotyped, and linkage to the pericentromeric region of chromosome 10 is reported (maximum pairwise lod score of 11.33 with 0% recombination between MEN2A and RBP3). These results demonstrate that both a locus for familial MTC and a locus for MEN 2B map to the pericentromeric region of chromosome 10, in the same region as a locus for MEN 2A. The finding that each of these three clinically distinct familial cancer syndromes maps to the same chromosomal region suggests that all are allelic mutations at the same locus or represent a cluster of genes involved in the regulation of neuroendocrine tissue development.
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PMID:Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A. 167 89

Multiple endocrine neoplasia type 2A (MEN2A) is a dominantly inherited cancer syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. The gene responsible for MEN2A was localized by linkage analysis to chromosome 10q11.2 in 1987, and recently mutations in RET, a proto-oncogene in the candidate region, were discovered in patients with MEN. The majority of mutations found so far in MEN2A patients have been located in nucleotide sequences encoding cysteine residues in the extracellular domain of RET. To characterize MEN2A germline alterations in the Japanese population, we screened DNA from eight unrelated patients for mutations in exons 10 and 11 of the RET proto-oncogene and found mutations in all eight patients, at codons 618, 620, or 634; each of these sites encodes a cysteine residue in the extracellular domain of RET. The mutations were confirmed in other affected individuals in the respective families by digestion of polymerase chain reaction (PCR) products containing the mutated codons with restriction enzymes (Rs alpha I, CfoI, or AluI) for which cleavage sites had been generated by the specific genetic alteration. These PCR-restriction enzyme systems will be useful for genetic diagnosis in members of families carrying these mutations.
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PMID:Germline mutations of the RET proto-oncogene in eight Japanese patients with multiple endocrine neoplasia type 2A (MEN2A). 786 65

Multiple endocrine neoplasia type 2 (MEN 2) is a cancer syndrome which comprises three related disorders, MEN type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC), MEN 2A is characterized by the association of MTC, a tumour arising from thyroid C-cells, pheochromocytoma and parathyroid hyperplasia. In addition to the thyroid cancer, MEN 2B associates pheochromocytoma, mucosal neuromas, ganglioneuromatosis of the digestive tract and skeletal abnormalities. In FMTC, the MTC is the sole clinical manifestation. MEN 2 is a dominantly inherited neural crest disorder caused by germline mutations of the RET proto-oncogene. The RET gene encodes a receptor tyrosine kinase, which displays a cadherin-like domain and a cysteine rich motif in its extracellular part. Missense mutations at one of five cysteines clustered in the extra-cytoplasmic domain of RET have been identified in the majority of the MEN 2A families and in two-thirds of FMTC. A single point mutation leading to the replacement of a methionine by a threonine within the tyrosine kinase domain has been detected in almost all cases of MEN 2B. We have screened 170 french MEN 2 families and a germline mutations in the RET gene have been identified in 92% of cases. Moreover, we confirmed the significant correlation between the nature, the position of the RET mutations and the clinical phenotype. The accurate identification by DNA testing of individual predisposed to MEN 2 suggests new protocols of treatment. Thyroidectomy as early as 6 years of age in individuals with MEN 2 mutations has been recently advocated by clinicians. We further provide evidence that MEN 2A and MEN 2B mutations convert the RET proto-oncogene in a dominantly-acting transforming gene due to the ligand-independent constitutive activation of the tyrosine kinase. Finally, we have constructed transgenic mice carrying the RET gene carrying a MEN 2A mutation fused to the calcitonin gene related peptide/calcitonin promoter. Animals of three independent transgenic lines developed C-cell hyperplasia and subsequently MTC with a complete penetrance. Taken together, these findings indicate that MEN 2A form of RET is oncogenic in thyroid C-cells, and suggest that these transgenic animals should prove a valuable model for hereditary MTC. Future work should yield insights in the signaling pathways subverted by the RET-MEN 2 proteins.
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PMID:[Neural crest and multiple endocrinopathies]. 907 21

Multiple endocrine neoplasia type 2 (MEN-2) is a familial cancer syndrome inherited in an autosomal dominant fashion with age-related penetrance. The main tumour type present in all manifestations of this syndrome. MEN-2A, MEN-2B and familial medullary thyroid carcinoma (FMTC), is medullary thyroid carcinoma (MTC). MTC arises from the parafollicular or C cells of the thyroid. MEN-2A is characterised by the triad of MTC, phaeochromocytoma, and parathyroid hyperplasia. MEN-2B is characterised by features similar to those of MEN-2A, except for the absence of clinically apparent parathyroid hyperplasia, and additional stigmata including a marfanoid habitus, mucosal neuromas and ganglioneuromatosis of the gastrointestinal tract. FMTC families have MTC as their only phenotype. Missense mutations affecting conserved cysteine codons adjacent to the transmembrane domain of the RET proto-oncogene have been identified in the germline DNA of patients with MEN-2A and FMTC. A single mutation at codon 918 in the tyrosine kinase domain of the RET receptor has been associated with the MEN-2B phenotype. In a small number of FMTC families, missense point mutations have also been identified in the intracellular domain of the RET protein. RET mutation analysis of MEN-2 families has allowed the identification of genotype-phenotype correlations. While 25% of all MTCs are hereditary, the great majority of MTCs, 75%, are sporadic. Various somatic RET mutations have been identified in sporadic MTCs. In a small number of hereditary MTCs with germline mutations in RET, an additional somatic missense RET mutation has been identified. The discovery of RET mutations in MEN-2 has made possible accurate DNA-based diagnosis and predictive testing. The clinical significance of somatic RET mutations has yet to be determined.
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PMID:RET proto-oncogene mutations in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma. 916 49

Causative germline missense mutations in the RET proto-oncogene have been associated with over 92% of families with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). MEN 2A is characterized primarily by medullary thyroid carcinoma (MTC) and pheochromocytoma, both tumors of neural crest origin. Parathyroid hyperplasia or adenoma is also seen in MEN 2A, but rarely in MEN 2B, which has additional stigmata, including a marfanoid habitus, mucosal neuromas, and ganglioneuromatosis of the gastrointestinal tract. In familial MTC, MTC is the only lesion present. Somatic RET mutations have also been identified in a subset of sporadic MTCs, pheochromocytomas, and rarely, small cell lung cancer, but not in sporadic parathyroid hyperplasias/adenomas or other neuroendocrine tumors. Glial cell line-derived neurotrophic factor (GDNF) and its receptor molecule GDNFR-alpha, have recently been identified as members of the RET ligand binding complex. Therefore, the genes encoding both GDNF and GDNFR-alpha are excellent candidates for a role in the pathogenesis of those MEN 2 families and sporadic neuroendocrine tumors without RET mutations. No mutations were found in the coding region of GDNF in DNA samples from 9 RET mutation negative MEN 2 individuals (comprising 6 distinct families), 12 sporadic MTCs, 17 sporadic cases of parathyroid adenoma, and 10 small cell lung cancer cell lines. Therefore, we find no evidence that mutation within the coding regions of GDNF plays a role in the genesis of MEN 2 and sporadic neuroendocrine tumors.
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PMID:Mutation analysis of glial cell line-derived neurotrophic factor, a ligand for an RET/coreceptor complex, in multiple endocrine neoplasia type 2 and sporadic neuroendocrine tumors. 928 37

Multiple Endocrine Neoplasia (MEN) is an inherited syndrome which appears in two major forms referred to as type 1 (MEN-1) and type 2 (MEN-2). MEN-1 is characterized by the occurrence of neuroendocrine parathyroid, pancreas, duodenum and pituitary lesions. In addition to these tumors adrenocortical, lipomatous and neuroendocrine tumors in other locations may develop. The genetic defect of MEN-1 has recently been identified and involves a new form of tumor suppressor gene called mu on chromosome 11q13. It codes for a protein called menin which is expressed in a variety of human tissues and organs. In MEN-1 gene carriers inactivating germline frameshift, nonsense, missense and in-frame deletion mutations scattered throughout the 10 coding exons have been identified. The MEN-2 syndrome is divided into three clinical variants referred to as MEN-2A, MEN-2B and familial medullary thyroid carcinoma (FMTC) which share medullary thyroid carcinomas as part of the disease phenotype. In MEN-2A pheochromocytomas and parathyroid hyperplasia and in MEN-2B additional skeletal abnormalities and ganglioneuromatosis may also be encountered. All three MEN-phenotypes are associated with oncogenic point mutations of the RET protooncogene on chromosome 10q11.2 which encodes a receptor-type tyrosine kinase. Its ligand--the glial cell line derived neurotropic factor (GDNF)--forms a signaling complex with the alpha type of the GDNF receptor. All neuroendocrine tumors of the different MEN-phenotypes may also occur sporadically and there are only few clinical and pathomorphological features which are helpful to discriminate sporadic from MEN-associated neuroendocrine neoplasms. The recent achievements of molecular pathology now allow for the unambiguous identification of MEN gene carriers among patients with neuroendocrine neoplasms by DNA testing for mutations in the mu and RET gene. In this overview, distinct macroscopic and histopathological features of the two MEN phenotypes will be summarized and most recent findings on the molecular pathology of these syndromes will be outlined, together with molecular methods to identify disease-gene carriers.
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PMID:Multiple endocrine neoplasia type 1 and 2: from morphology to molecular pathology 1997. 947 63

Multiple endocrine neoplasia type 1 (MEN 1), and the multiple endocrine neoplasia type 2 syndromes (MEN 2A, MEN 2B, and familial non-MEN medullary thyroid carcinoma [FMTC]) encompass a wide range of endocrine problems, but arise from only two genes: the MEN 1 tumor suppressor gene and the RET proto-oncogene. MEN 1 is characterized by parathyroid hyperplasia, pancreaticoduodenal neuroendocrine tumors (PNTs), and pituitary adenomas. Surgery is the principal treatment modality for hyperparathyroidism and PNTs, but questions still remain concerning the timing and extent of surgery for PNTs. The MEN 2 syndromes are characterized by complete penetrance of medullary thyroid cancer. The MEN 2 syndromes differ in their variable expression of hyperparathyroidism, pheochromocytomas, and other clinical features. Genetic testing for mutations in the RET gene has revolutionized treatment by enabling thyroidectomies before significant disease occurs.
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PMID:Multiple endocrine neoplasias. 1080 54

Germline mutations of the MEN1 gene are found in more than 85% of multiple endocrine neoplasia type 1 (MEN 1) patients, and germline mutations of the RET gene are found in more than 95% of multiple endocrine neoplasia type 2 (MEN2) patients. Parathyroid hyperplasia is seen in more than 90% of MEN 1 and about 15% of MEN2A patients. To date, somatic MEN1 mutations are reported in about 20% of sporadic parathyroid tumors. To elucidate the genetic basis of parathyroid tumor development, we examined somatic RET gene mutations in sporadic parathyroid tumors and hyperplasia secondary to uremia, and somatic MEN1 gene mutations in parathyroid hyperplasia from MEN2A patients. A total of 145 parathyroid tumors comprising 129 sporadic parathyroid tumors, 14 hyperplastic lesions secondary to uremia, and two hyperplastic lesions from MEN2A patients were examined. DNA was extracted from fresh frozen parathyroid tissue. Exons 2-10 of the MEN1 gene and exons 10 and 11 of the RET gene were sequenced. No somatic RET gene mutations were found in the 129 sporadic parathyroid tumors or 14 parathyroid hyperplastic lesions secondary to uremia. No somatic MEN1 gene mutations were found in the two parathyroid hyperplasia from MEN2A patients. These data suggest that RET gene mutation may not be involved in the development of sporadic parathyroid tumors and hyperplasia secondary to uremia and that MEN1 gene mutation may not be or is rarely associated with development of parathyroid hyperplasia in MEN2A patients.
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PMID:Absence of somatic RET gene mutation in sporadic parathyroid tumors and hyperplasia secondary to uremia, and absence of somatic Men1 gene mutation in MEN2A-associated hyperplasia. 1091 3

Germ line mutations of the RET proto-oncogene are responsible for the development of multiple endocrine neoplasia type 2A (MEN 2A), an inherited cancer syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. To study the mechanism of tissue-specific tumor development by RET with a MEN2A (cysteine 634-->arginine) mutation, we generated transgenic mice by introducing the RET-MEN2A gene fused to Moloney murine leukemia virus long terminal repeat. Expression of the transgene and its product was detected at variable levels in a variety of tissues including thyroid, heart, liver, colon, parotid gland, and brain. All of 29 mice analyzed developed thyroid C-cell hyperplasia or medullary carcinoma, accompanying high levels of serum calcitonin. In addition, development of mammary or parotid gland adenocarcinoma was observed in one-half of the transgenic mice. RET dimerization and its complex formation with Shc and Grb2 adaptor proteins were detected in tumor tissues. Unexpectedly, no tumor formation was found in other tissues despite RET-MEN2A expression where RET dimerization was undetectable. Because these tissues but not tumors expressed glial cell line-derived neurotrophic factor family receptor alpha (GFR alpha) at high levels, this suggested that GFR alpha expression may interfere in the dimerization of the RET-MEN2A mutant proteins, leading to tissue-specific tumor development in vivo.
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PMID:Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation. 1101 55

A 59-year-old woman who had parathyroid adenoma, parathyroid hyperplasia, thyroid follicular adenoma, thyroid papillary carcinoma, astrocytoma of the right temporal lobe, cerebellar meningioma, capillary hemangioma of the left external auditory meatus and papilloma of the left upper gingiva is reported. Dynamic magnetic resonance imaging, computed tomography with contrast-enhancement and gastrofiberscopy revealed no remarkable findings in the pituitary, pancreas, adrenals, stomach or duodenum. Similar lesions were not found in any family members. Defect of the causative genes of multiple endocrine neoplasia types I and IIa, MENIN and RET was not detected. Further follow-up of this patient and family members is needed.
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PMID:Undefined complications of parathyroid adenoma, parathyroid hyperplasia (primary hyperparathyroidism), thyroid follicular adenoma, thyroid papillary carcinoma, temporal astrocytoma, cerebellar meningioma, and hemangioma of external auditory meatus and oral papilloma. 1103 Feb 6


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