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)

Multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited cancers that have in common the clinical feature of medullary thyroid carcinoma (MTC). We have performed both genomic long-range restriction mapping and yeast artificial chromosome (YAC) contig assembly and restriction mapping to establish physical linkage, order, and distances between six loci in 10q11.2 near the genes responsible for these hereditary cancers. RET, D10S94, D10S182, and D10S102 have been mapped in genomic DNA. RET, D10S94, D10S182, D10F38S3, and the 10q11.2 sequences detected by DNA marker DM124 are encompassed by a 1-Mb YAC contig. Six physically linked loci are within 1.4 Mb and have an order and orientation of 10cen, D10F38S3, DM124, RET, D10S94, D10S182, D10S102, 10qter. Mutations in the RET proto-oncogene have recently been demonstrated to be associated with MEN 2A and FMTC. RET is located within a genetically defined MEN2A candidate interval between D10S141 and D10S94; MEN2B has been mapped to a larger, overlapping region between D10S141 and a more distal locus, RBP3. Both our genomic physical map and our YAC contig span the entire MEN2A candidate region and overlap with that of MEN2B. These maps will facilitate the identification of genes that can be considered candidates for MEN2B and the identification of tumor-specific alterations important in sporadic MTC.
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PMID:Genomic and yeast artificial chromosome long-range physical maps linking six loci in 10q11.2 and spanning the multiple endocrine neoplasia type 2A (MEN2A) region. 790 24

Using a PCR strategy based on an initial set of 15 couples of primers designed from the known cDNA sequence, we identified 18 introns in the human RET proto-oncogene and sequenced the corresponding 5' and 3' exon-intron junctions. This approach was successful in locating all the introns contained in fragments short enough to be amplified by PCR. Thus 19 exons were identified which, together with the previously reported exon subjected to alternative splicing, brings the total number of RET exons to 20. This information is relevant for the screening of recently reported missense mutations of RET which cause Multiple Endocrine Neoplasia 2A (MEN2A) and for the search of additional point mutations of the same gene which might cause two other neural crest disorders, MEN2B and Hirschsprung disease, mapping in the same region as MEN2A.
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PMID:Exon structure and flanking intronic sequences of the human RET proto-oncogene. 790 7

Tight linkage with the RET proto-oncogene (Zmax = 3.41 at theta = 0.00), analysis of recombinants and detection of a familial microdeletion in a large pedigree restrict the mapping of the Hirschsprung (HSCR) gene previously localized on proximal 10q. The molecular characterization of the familial microdeletion and of 3 additional cytogenetically visible de novo deletions, isolated in somatic cell hybrids, identify a smallest region of overlap of 250 Kb. This contains the RET proto-oncogene where missense mutations causing multiple endocrine neoplasia type 2A (MEN 2A) phenotype were recently found. The pentagastrin test (which detects preclinical forms of MEN 2A or B) is negative in adult HSCR patients with deletions of the RET gene. This represents a good candidate for the search of mutations causing HSCR.
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PMID:Close linkage with the RET protooncogene and boundaries of deletion mutations in autosomal dominant Hirschsprung disease. 790 8

An overlapping set of 21 yeast artificial chromosomes (YACs) spanning the RET proto-oncogene [Takahashi et al., Oncogene 3 (1988) 571-578] and D10S102 markers on human chromosome 10 was isolated in a series of hybridization-based chromosomal walks in a YAC library. Genetic linkage analyses implicate this chromosomal region as the location of the gene (MEN2A) responsible for multiple endocrine neoplasia type 2A. Four YACs carrying a RET sequence-tagged site (STS) and two YACs carrying a D10S102 STS were used to initiate chromosome walks. These were based on hybridization of Alu element-mediated polymerase chain reaction (Alu-PCR) products from YACs to dot blots of Alu-PCR products from complex pools of YAC clones. The hybridization anchor content of YACs identified in the walks was confirmed by probing blots of Alu-PCR products from individual YACs and by comparing Alu-PCR fingerprints of each YAC. Ten hybridization-based Alu-PCR anchors and three STS anchors were ordered within eleven intervals created by the 21 overlapping YACs. The order of anchors requiring the fewest gaps in the YACs is consistent with the walking results and establishes the STS anchor order as D10S102-D10S94-RET. The overlapping set of YACs represents about 1.55 Mb of the human genome according to restriction mapping of four representative YACs in the contig. These results demonstrate the power of Alu-PCR hybridization for chromosomal walking and provide a rich source of overlapping YACs which can be used to identify candidate MEN2A genes.
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PMID:Rapid identification of overlapping YACs in the MEN2 region of human chromosome 10 by hybridization with Alu element-mediated PCR products. 790 72

Multiple endocrine neoplasia type 2B (MEN 2B) is a human cancer syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytomas, mucosal neuromas, ganglioneuromas of the intestinal tract, and skeletal and ophthalmic abnormalities. It appears both as an inherited disorder and as de novo disease. Sequence analysis of germ-line DNA from MEN 2B patients revealed the existence of the same point mutation in the RET protooncogene in 34 unrelated individuals. This sequence difference was not observed in 93 unaffected individuals, including the normal parents of 14 de novo MEN 2B patients. The mutation (ATG-->ACG) results in the replacement of methionine with threonine within the catalytic core region of the tyrosine kinase domain. We propose that this amino acid replacement effects substrate interactions and results in dominant oncogenic activity by the RET protein. Missense mutations in the extracellular ligand-binding domain of the RET protooncogene previously have been associated with two other disorders [MEN 2A and familial MTC (FMTC)] in which MTC is observed. MEN 2B represents the third form of heritable MTC known to be an allele of RET. Alterations in two different functional domains of the putative receptor protein tyrosine kinase are implicated in development of MTC.
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PMID:Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. 790 17

We have analysed 118 families with inherited medullary thyroid carcinoma (MTC) for mutations of the RET proto-oncogene. These included cases of multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B) and familial MTC (FMTC). Mutations at one of 5 cysteines in the extracellular domain were found in 97% of patients with MEN 2A and 86% with FMTC but not in MEN 2B patients or normal controls. 84% of the MEN2A mutations affected codon 634. MEN 2A patients with a Cys634 to Arg substitution had a greater risk of developing parathyroid disease than those with other codon 634 mutations. Our data show a strong correlation between disease phenotype and the nature and position of the RET mutation, suggesting that a simple, constitutive activation of the RET tyrosine kinase is unlikely to explain the events leading to MEN 2A and FMTC.
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PMID:Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. 790 13

Ten kindreds (95 individuals) with multiple endocrine neoplasia, type 2 (MEN 2) were analyzed by linkage analysis using four highly polymorphic (CA)n-repeat markers (sTCL-1, D10S141, ZNF22, and sJRH-1). Additionally, we examined the RET proto-oncogene for specific mutations by DNA sequence analyses in these 10 plus 14 members of 3 additional kindred. Nine families had MEN 2A, two had MEN 2B, and two had medullary thyroid cancer alone (FMTC). Using these four markers, all 10 kindreds were informative, with 10 individuals predicted to be presymptomatic MEN 2 gene carriers and 23 individuals predicted not to be carriers. DNA sequence analysis of exons 10 and 11 of the RET proto-oncogene revealed a mutation in all nine MEN 2A kindreds. A missense mutation was found in each case, leading to a loss of a cysteine residue (codon 618 of exon 10 or codon 634 of exon 11). In the MEN 2A families, the linkage analysis and RET mutation analysis gave concordant results for prediction of gene carriers in 100% of the individuals tested. No mutations were found in the two kindreds with FMTC or the two MEN 2B kindreds. Two individuals from two different MEN 2A kindreds were identified who had abnormal calcitonin stimulation tests but were not MEN 2A gene carriers by both linkage analysis and RET mutation analysis. These individuals presumably represented the sporadic occurrence of abnormal calcitonin stimulation tests in the general population. These studies provide further support for a role of the RET proto-oncogene in the pathogenesis of MEN 2A. Additionally, in the absence of identifiable RET proto-oncogene mutations, linkage analysis using (CA)n-repeat markers is a highly accurate alternative for the identification of MEN 2 or FMTC gene carriers.
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PMID:Identification of multiple endocrine neoplasia, type 2 gene carriers using linkage analysis and analysis of the RET proto-oncogene. 790 18

Multiple endocrine neoplasia (MEN) type 2A (MEN 2A) and type 2B (MEN 2B) are dominantly inherited with a predisposition to endocrine tumors. The responsible genes for MEN 2A and 2B have recently been localized to chromosome 10q 11.2 by genetic and physical mapping. The DNA segment encompasses the RET proto-oncogene. This is a receptor tyrosine kinase gene, which is expressed in medullary thyroid carcinoma and pheochromocytoma. Point mutations in the cysteine-rich domain of the RET were demonstrated in patients with MEN 2A. The cosegregation of these mutations and disease in MEN 2A families indicates that they possess a predisposition endocrine organs to develop into tumors. Biological assessment of the mutant forms in cell culture and transgenic mouse lines should provide further insight as to the role of the RET in the tumor development.
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PMID:[The molecular genetics of multiple endocrine neoplasia type 2A and 2B]. 791 Aug 61

Patients with MEN 2A, MEN 2B, and familial non-MEN medullary thyroid carcinoma (MTC) inherit MTC in an autosomal dominant fashion. This malignancy has been diagnosed previously by detecting elevated plasma calcitonin levels, a tumor marker for MTC, following the intravenous administration of secretagogues. Although the study of large pedigrees with MEN 2A, using highly informative flanking markers and linkage analysis, are highly accurate in predicting the inheritance of the disease, the method is indirect and somewhat cumbersome. Mutations in the RET proto-oncogene have been identified independently in patients with MEN 2A and familial medullary thyroid carcinoma. Even though the RET mutations are inherited with disease, there is no direct evidence that the mutations cause the MEN 2 syndromes. The usefulness of molecular methods in the diagnosis and treatment of patients with these syndromes is discussed, and a strategy for deciding operative intervention is presented.
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PMID:Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes. 791 27

The occurrence of mutations in the RET protooncogene has been investigated in 12 multiple endocrine neoplasia type 2A families and 18 cases of sporadic thyroid medullary carcinomas and pheochromocytomas. Ten of 12 families showed single base substitutions in the RET protooncogene exons 10 and 11, coding for the extracellular domain of the protein. Tumor tissues from 2 multiple endocrine neoplasia type 2A patients were analyzed at the DNA and ribonucleic acid levels and revealed the same heterozygous mutations found in the peripheral blood lymphocytes. This demonstrates that both the normal and mutant alleles are expressed. No mutations in these exons were detected in the 18 cases of sporadic tumors investigated. These data provided further evidence that the mutated RET protooncogene acts in a dominant fashion and is responsible for the pathogenesis of this syndrome.
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PMID:Frequent RET protooncogene mutations in multiple endocrine neoplasia type 2A. 791 36


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