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)

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

Following the recent identification of specific germline mutations of the RET proto-oncogene in Multiple Endocrine Neoplasia type 2A (MEN2A) patients, we looked for mutations of this gene in a pedigree showing recurrence of MEN2A and localized Cutaneous Lichen Amyloidosis (CLA). Basal calcitonin and/or pentagastrin test performed in all the 10 available members of this pedigree confirmed the clinical diagnosis and allowed the presymptomatic identification of an additional carrier. A cys634-->tyr missense mutation, already reported as causative in MEN2A patients, was identified after SSCP analysis and direct sequencing of exon 11 of the RET protooncogene in one individual affected with both MEN2A and CLA, thus suggesting a common etiology for the two disorders. Taking advantage of the observation of an RsaI restriction site in the sequence surrounding the mutated codon, we could demonstrate that the same mutation is present in three other affected members, in the presymptomatic carrier and in one additional 25 years old healthy member who shows a mildly positive pentagastrin test.
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PMID:Identification of the Cys634-->Tyr mutation of the RET proto-oncogene in a pedigree with multiple endocrine neoplasia type 2A and localized cutaneous lichen amyloidosis. 791 13

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are two closely related cancer syndromes inherited in an autosomal dominant manner. Mutations in the RET proto-oncogene were found in MEN 2A and FMTC families. In this study we report seven different germline mutations in the RET proto-oncogene in five of five MEN 2A and five of six FMTC families. Each of the mutations involves a cysteine residue in the extracellular cysteine-rich domain of the RET receptor tyrosine kinase. We developed simple polymerase chain reaction based diagnostic tests for all seven mutations in these families.
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PMID:Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. 791 65

Mutations in the RET proto-oncogene have been identified in the constitutional DNA of patients with the inherited disorders multiple endocrine neoplasia type 2A and 2B and familial medullary thyroid carcinoma. This review focuses on the discoveries over the past year that pointed to RET as a candidate gene, and on the nature and spectrum of what appear to be dominant mutations associated with an inherited predisposition to tumor development.
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PMID:Inherited cancers associated with the RET proto-oncogene. 791 23

Hirschsprung's disease (HSCR) is a common condition (1 in 5,000 live births) resulting in intestinal obstruction in neonates and megacolon in infants and adults. This disease has been ascribed to the absence of autonomic ganglion cells, which are derived from the neural crest, in the terminal hindgut. Segregation analyses have suggested incompletely penetrant dominant inheritance in familial HSCR. Recently, a gene for HSCR has been mapped to chromosome 10q11.2. No recombination was observed between the disease locus and the locus for the RET proto-oncogene, a protein tyrosine kinase gene expressed in the cells derived from the neural crest. Here we report on nonsense and missense mutations in the extracellular domain of the RET protein (exons 2, 3, 5 and 6) in 6 unrelated probands and show that the mutant genotypes segregate with the disease in HSCR families. Mutations of RET have been previously reported in multiple endocrine neoplasia type 2A (MEN 2A). Thus, germ-line mutations of the RET gene may contribute either to developmental anomalies in HSCR or to inherited predisposition to cancer in MEN 2A.
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PMID:[Mutations of RET proto-oncogene in Hirschsprung disease]. 800 Sep 15

H4(D10S170) is a gene which we isolated because of its frequent rearrangement with the RET proto-oncogene in vivo. Its fusion to RET generates the RET/PTC1 oncogene, which has been detected in about 20% of human thyroid papillary carcinomas. We have cloned and sequenced the cDNA corresponding to the H4(D10S170) gene from a human normal thyroid cDNA library. The nucleotide sequence of the H4(D10S170) 3 kb transcript shows no significant homology to known genes and contains an open reading frame (ORF) of 585 amino acids. H4(D10S170) predicted protein has no transmembrane domain and shows extensive regions in the alpha helical conformation, which are 30% homologous to the alpha-helical domains of several proteins including tropomyosin, vimentin, keratin and the tail region of myosin heavy chain. A putative SH3 binding site is present at the carboxy terminus, which suggests that H4(D10S170) might be a cytoskeletal protein.
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PMID:Cloning and characterization of H4 (D10S170), a gene involved in RET rearrangements in vivo. 805 16

Recently identified mutations affecting different domains of the RET proto-oncogene are associated with Multiple Endocrine Neoplasia type 2A (MEN 2A) and type 2B (MEN 2B), familial and sporadic Medullary Thyroid Carcinomas (MTC) and Hirschsprung disease (HSCR). In order to facilitate the screening for RET mutations, and to study possible genotype-phenotype correlations, we established exon-intron junctions and extended the intronic sequences flanking the 20 exons of this gene. This made it possible to design primers and to develop PCR conditions useful for SSCP analysis of the whole RET coding sequence. Nine conformational variants were observed which after sequencing turned out to be 8 silent mutations and a conservative amino acid substitution. Restriction analysis performed on DNA samples from unrelated controls confirmed the polymorphic nature of six of these nucleotide changes and made it possible to estimate the frequency of the corresponding alleles.
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PMID:DNA polymorphisms and conditions for SSCP analysis of the 20 exons of the ret proto-oncogene. 770 Jun 53

Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome that affects tissues derived from neural ectoderm. It is characterized by medullary thyroid carcinoma (MTC) and phaeochromocytoma. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10q11.2 (refs 2,3). The DNA segment encompasses the RET proto-oncogene, a receptor tyrosine kinase gene expressed in MTC and phaeochromocytoma and at lower levels in normal human thyroid. This suggested RET as a candidate for the MEN2A gene. We have identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls. Further, 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of the RET extracellular and transmembrane domains.
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PMID:Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. 809 2


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