Molekulargenetisches Labor
Zentrum für Nephrologie und Stoffwechsel
Moldiag Erkrankungen Gene Support Kontakt

Ret Proto-Oncogen

Das RET-Gen kodiert eine Rezeptor-Tyrosinkinase, welche eine wichtige Rolle bei der Signaltransduktion während Wachstum und Differenzierung spielt. Deshalb wurden Mutationen bei verschiedenen Erkrankungen der Zellregulation gefunden. So bei der multiplen endokrinen Neoplasie Typ IIA und IIB, Hirscsprung-Erkrankung, medullärem Schilddrüsencarcinom und renaler Nierenadysplasie.

Interpretation

Gain-of-function Mutationen sind für die multiple endokrine Neoplasie (MEN) verantwortlich. Betrifft die Mutation eines der Cysteinreste der extrazellulären oder intramembranäsen Domäne so kommt es zur Ausbildung von MEN Typ 2A. Weil durch die Mutation eines der beiden Reste ein stabilisierende intramolekulare Disulfidbrückenbildung nicht mehr möglich ist kommt es zur Bildung einer intermolekularen Disulfidbrücke mit einem anderen mutierten Protein. Diese Dimerbildung signalisiert jedoch eine Aktivierung des Rezeptors. Eine ähnliche Artivierung liegt bei Mutationen des Tyrosinrestes in der intrazellulären Domäne vor.Hierdurch entsteht der noch schwerere Phenotyp MEN 2B.

Loss-of-function Mutationen führen zu Morbus Hirschsprung.

Während die beiden für die endokrine Neoplasien (MEN) verantwortlichen gain-of-function Mutationen ausschließlich in der männlichen Keimbahn entstehen. Trenten die für Morbus Hirschsprung verantwortlichen Mutationen ausschließlich in der weiblichen Keimbahn auf.

Gentests:

Klinisch Untersuchungsmethoden Familienuntersuchung
Bearbeitungszeit 5 Tage
Probentyp genomische DNS
Klinisch Untersuchungsmethoden Hochdurchsatz-Sequenzierung
Bearbeitungszeit 25 Tage
Probentyp genomische DNS
Klinisch Untersuchungsmethoden Direkte Sequenzierung der proteinkodierenden Bereiche eines Gens
Bearbeitungszeit 25 Tage
Probentyp genomische DNS
Klinisch Untersuchungsmethoden Multiplex ligationsabhängige Amplifikation
Bearbeitungszeit 25 Tage
Probentyp genomische DNS

Verknüpfte Erkrankungen:

Renale Hypodysplasie/Aplasie 1
DSTYK
ITGA8
PAX2
RET
UPK3A
Phäochromozytom
GDNF
KIF1B
MAX
OCLN
RET
SDHB
SDHD
TMEM127
VHL
Familiäres meduläres Schilddrüsenkarzinom
NTRK1
RET

Referenzen:

1.

None (1997) Human cancer syndromes: clues to the origin and nature of cancer.

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2.

Amiel J et al. (1998) Mutations of the RET-GDNF signaling pathway in Ondine's curse.

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3.

Japón MA et al. (2002) Glial-derived neurotropic factor and RET gene expression in normal human anterior pituitary cell types and in pituitary tumors.

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4.

Neumann HP et al. (2002) Germ-line mutations in nonsyndromic pheochromocytoma.

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5.

Amiel J et al. (2003) Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.

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6.

Iwashita T et al. (2003) Hirschsprung disease is linked to defects in neural crest stem cell function.

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7.

Ceccherini I et al. (1994) 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.

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8.

Hofstra RM et al. (1996) RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia.

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9.

Seri M et al. (1997) A Cys634Gly substitution of the RET proto-oncogene in a family with recurrence of multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis.

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10.

Farndon JR et al. (1986) Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity.

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Loré F et al. (2000) Unilateral renal agenesis in a family with medullary thyroid carcinoma.

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Cote GJ et al. (2003) Lessons learned from the management of a rare genetic cancer.

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13.

de Pontual L et al. (2006) Mutations of the RET gene in isolated and syndromic Hirschsprung's disease in human disclose major and modifier alleles at a single locus.

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14.

Neumann HP et al. (2007) Evidence of MEN-2 in the original description of classic pheochromocytoma.

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15.

Eng C et al. (1995) Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas.

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16.

Klugbauer S et al. (1998) Detection of a novel type of RET rearrangement (PTC5) in thyroid carcinomas after Chernobyl and analysis of the involved RET-fused gene RFG5.

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17.

Klugbauer S et al. (1999) The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas.

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18.

Pierotti MA et al. (1992) Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC.

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19.

Santoro M et al. (1992) Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype.

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20.

Dang GT et al. (1999) A codon 891 exon 15 RET proto-oncogene mutation in familial medullary thyroid carcinoma: a detection strategy.

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21.

Auricchio A et al. (1999) Double heterozygosity for a RET substitution interfering with splicing and an EDNRB missense mutation in Hirschsprung disease.

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22.

Pigny P et al. (1999) A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma.

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23.

Nakata T et al. (1999) Fusion of a novel gene, ELKS, to RET due to translocation t(10;12)(q11;p13) in a papillary thyroid carcinoma.

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24.

Fitze G et al. (1999) Association of RET protooncogene codon 45 polymorphism with Hirschsprung disease.

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25.

Tessitore A et al. (1999) A novel case of multiple endocrine neoplasia type 2A associated with two de novo mutations of the RET protooncogene.

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26.

Borrego S et al. (1999) Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression.

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27.

Smith-Hicks CL et al. (2000) C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B.

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28.

Bordeaux MC et al. (2000) The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease.

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29.

Borrego S et al. (2000) RET genotypes comprising specific haplotypes of polymorphic variants predispose to isolated Hirschsprung disease.

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30.

Griseri P et al. (2000) A single-nucleotide polymorphic variant of the RET proto-oncogene is underrepresented in sporadic Hirschsprung disease.

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31.

Munnes M et al. (2000) Familial form of hirschsprung disease: nucleotide sequence studies reveal point mutations in the RET proto-oncogene in two of six families but not in other candidate genes.

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32.

Salvatore D et al. (2000) Tyrosines 1015 and 1062 are in vivo autophosphorylation sites in ret and ret-derived oncoproteins.

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33.

Huang SC et al. (2000) Duplication of the mutant RET allele in trisomy 10 or loss of the wild-type allele in multiple endocrine neoplasia type 2-associated pheochromocytomas.

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34.

Batourina E et al. (2001) Vitamin A controls epithelial/mesenchymal interactions through Ret expression.

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35.

Machens A et al. (2001) Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties.

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36.

Klugbauer S et al. (2001) RET rearrangements in radiation-induced papillary thyroid carcinomas: high prevalence of topoisomerase I sites at breakpoints and microhomology-mediated end joining in ELE1 and RET chimeric genes.

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37.

Melillo RM et al. (2001) Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade.

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38.

Julies MG et al. (2001) Novel RET mutations in Hirschsprung's disease patients from the diverse South African population.

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39.

Niccoli-Sire P et al. (2001) Familial medullary thyroid carcinoma with noncysteine ret mutations: phenotype-genotype relationship in a large series of patients.

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40.

de Graaff E et al. (2001) Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis.

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41.

Ruiz A et al. (2001) Germline sequence variant S836S in the RET proto-oncogene is associated with low level predisposition to sporadic medullary thyroid carcinoma in the Spanish population.

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42.

Koch CA et al. (2001) Allelic imbalance of the mutant and wild-type RET allele in MEN 2A-associated medullary thyroid carcinoma.

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43.

Menko FH et al. (2002) Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918.

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44.

Lombardo F et al. (2002) Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804.

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45.

Gabriel SB et al. (2002) Segregation at three loci explains familial and population risk in Hirschsprung disease.

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46.

Carter MT et al. (2001) Conservation of RET proto-oncogene splicing variants and implications for RET isoform function.

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47.

Antiñolo G et al. (2002) A novel germline point mutation, c.2304 G-->T, in codon 768 of the RET proto-oncogene in a patient with medullary thyroid carcinoma.

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48.

Batourina E et al. (2002) Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret.

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49.

Griseri P et al. (2002) A rare haplotype of the RET proto-oncogene is a risk-modifying allele in hirschsprung disease.

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50.

Carrasquillo MM et al. (2002) Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease.

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51.

Nunes AB et al. (2002) A novel Val648Ile substitution in RET protooncogene observed in a Cys634Arg multiple endocrine neoplasia type 2A kindred presenting with an adrenocorticotropin-producing pheochromocytoma.

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52.

Borrego S et al. (2003) A founding locus within the RET proto-oncogene may account for a large proportion of apparently sporadic Hirschsprung disease and a subset of cases of sporadic medullary thyroid carcinoma.

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53.

Huang SC et al. (2003) Amplification and overexpression of mutant RET in multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma.

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54.

Patócs A et al. (2003) Segregation of the V804L mutation and S836S polymorphism of exon 14 of the RET gene in an extended kindred with familial medullary thyroid cancer.

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55.

Puñales MK et al. (2003) RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome.

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56.

Kjaer S et al. (2003) Intrinsic susceptibility to misfolding of a hot-spot for Hirschsprung disease mutations in the ectodomain of RET.

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57.

McWhinney SR et al. (2003) Intronic single nucleotide polymorphisms in the RET protooncogene are associated with a subset of apparently sporadic pheochromocytoma and may modulate age of onset.

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58.

Fitze G et al. (2003) Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR).

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59.

Da Silva AM et al. (2003) A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma.

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60.

Burzynski GM et al. (2004) Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2.

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61.

Jimenez C et al. (2004) A novel point mutation of the RET protooncogene involving the second intracellular tyrosine kinase domain in a family with medullary thyroid carcinoma.

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62.

Elisei R et al. (2004) RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population.

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63.

Jimenez C et al. (2004) Pheochromocytoma and medullary thyroid carcinoma: a new genotype-phenotype correlation of the RET protooncogene 891 germline mutation.

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64.

Jijiwa M et al. (2004) A targeting mutation of tyrosine 1062 in Ret causes a marked decrease of enteric neurons and renal hypoplasia.

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65.

Garcia-Barcelo M et al. (2005) TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease.

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66.

Schuetz G et al. (2004) The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells.

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67.

Lesueur F et al. (2005) Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients.

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68.

Burzynski GM et al. (2005) Identifying candidate Hirschsprung disease-associated RET variants.

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69.

Fernandez RM et al. (2005) Ancestral RET haplotype associated with Hirschsprung's disease shows linkage disequilibrium breakpoint at -1249.

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70.

Machens A et al. (2005) Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2.

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71.

Emison ES et al. (2005) A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk.

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72.

Frank-Raue K et al. (2005) Coincidence of multiple endocrine neoplasia types 1 and 2: mutations in the RET protooncogene and MEN1 tumor suppressor gene in a family presenting with recurrent primary hyperparathyroidism.

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73.

Kashuk CS et al. (2005) Phenotype-genotype correlation in Hirschsprung disease is illuminated by comparative analysis of the RET protein sequence.

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74.

Cebrian A et al. (2005) Polymorphisms in the initiators of RET (rearranged during transfection) signaling pathway and susceptibility to sporadic medullary thyroid carcinoma.

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75.

Baumgartner-Parzer SM et al. (2005) Polymorphisms in exon 13 and intron 14 of the RET protooncogene: genetic modifiers of medullary thyroid carcinoma?

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76.

Fisher S et al. (2006) Conservation of RET regulatory function from human to zebrafish without sequence similarity.

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77.

Plaza-Menacho I et al. (2006) Current concepts in RET-related genetics, signaling and therapeutics.

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78.

Griseri P et al. (2007) A common variant located in the 3'UTR of the RET gene is associated with protection from Hirschsprung disease.

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79.

Ruiz-Ferrer M et al. (2006) A complex additive model of inheritance for Hirschsprung disease is supported by both RET mutations and predisposing RET haplotypes.

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80.

Veiga-Fernandes H et al. (2007) Tyrosine kinase receptor RET is a key regulator of Peyer's patch organogenesis.

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81.

Elisei R et al. (2007) RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center.

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82.

Elisei R et al. (2008) Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study.

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83.

Skinner MA et al. (2008) Renal aplasia in humans is associated with RET mutations.

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84.

Yang Y et al. (2008) RET Gly691Ser mutation is associated with primary vesicoureteral reflux in the French-Canadian population from Quebec.

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85.

Miao X et al. (2010) Reduced RET expression in gut tissue of individuals carrying risk alleles of Hirschsprung's disease.

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86.

Emison ES et al. (2010) Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability.

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87.

Ikeda I et al. (1990) Specific expression of the ret proto-oncogene in human neuroblastoma cell lines.

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88.

Grieco M et al. (1990) PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas.

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89.

Takahashi M et al. (1989) Isolation of ret proto-oncogene cDNA with an amino-terminal signal sequence.

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90.

Ishizaka Y et al. (1989) Human ret proto-oncogene mapped to chromosome 10q11.2.

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91.

Mendonça BB et al. (1988) Cushing's syndrome due to ectopic ACTH secretion by bilateral pheochromocytomas in multiple endocrine neoplasia type 2A.

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92.

Takahashi M et al. (1985) Activation of a novel human transforming gene, ret, by DNA rearrangement.

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93.

Takahashi M et al. (1988) Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains.

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94.

Pasini B et al. (1995) The physical map of the human RET proto-oncogene.

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95.

Eng C et al. (1995) Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma.

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96.

Attié T et al. (1995) Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease.

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97.

Mendelsohn C et al. (1994) Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants.

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98.

Angrist M et al. (1995) Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease.

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99.

Bolino A et al. (1995) RET mutations in exons 13 and 14 of FMTC patients.

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100.

Santoro M et al. (1995) Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B.

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101.

Eng C et al. (1995) A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC.

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102.

Gardner E et al. (1994) Haplotype analysis of MEN 2 mutations.

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103.

Luo Y et al. (1993) Close linkage with the RET protooncogene and boundaries of deletion mutations in autosomal dominant Hirschsprung disease.

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104.

Carlson KM et al. (1994) Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B.

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105.

None (1994) Genetics. One gene--four syndromes.

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106.

Hofstra RM et al. (1994) A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.

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107.

Mulligan LM et al. (1994) Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC.

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108.

Eng C et al. (1994) Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours.

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109.

Xue F et al. (1994) Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests.

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110.

Carlson KM et al. (1994) Parent-of-origin effects in multiple endocrine neoplasia type 2B.

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111.

Puffenberger EG et al. (1994) A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease.

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112.

Ceccherini I et al. (1994) DNA polymorphisms and conditions for SSCP analysis of the 20 exons of the ret proto-oncogene.

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113.

Lairmore TC et al. (1993) A 1.5-megabase yeast artificial chromosome contig from human chromosome 10q11.2 connecting three genetic loci (RET, D10S94, and D10S102) closely linked to the MEN2A locus.

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114.

Mulligan LM et al. (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.

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115.

Donis-Keller H et al. (1993) Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

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116.

Romeo G et al. (1994) Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease.

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117.

Edery P et al. (1994) Mutations of the RET proto-oncogene in Hirschsprung's disease.

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118.

Schuchardt A et al. (1994) Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret.

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119.

Pachnis V et al. (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis.

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120.

Rodrigues GA et al. (1993) Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase.

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121.

None (1996) Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease.

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122.

Bolk S et al. (1996) Congenital central hypoventilation syndrome: mutation analysis of the receptor tyrosine kinase RET.

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123.

Höppener JW et al. (1996) RET receptor tyrosine kinase gene mutations: molecular biological, physiological and clinical aspects.

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124.

Iwashita T et al. (1996) Mechanism of ret dysfunction by Hirschsprung mutations affecting its extracellular domain.

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125.

Eng C et al. (1997) Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease.

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126.

Seri M et al. (1997) Frequency of RET mutations in long- and short-segment Hirschsprung disease.

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127.

Höppner W et al. (1997) A duplication of 12 bp in the critical cysteine rich domain of the RET proto-oncogene results in a distinct phenotype of multiple endocrine neoplasia type 2A.

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128.

Boccia LM et al. (1997) Mutation of RET codon 768 is associated with the FMTC phenotype.

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129.

Decker RA et al. (1998) Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation.

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130.

Hofstra RM et al. (1997) A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma.

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131.

Pelet A et al. (1998) Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease.

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132.

Berndt I et al. (1998) A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A.

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133.

Cetta F et al. (1998) The ret/ptc1 oncogene is activated in familial adenomatous polyposis-associated thyroid papillary carcinomas.

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134.

Bongarzone I et al. (1998) Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation.

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135.

Shirahama S et al. (1998) Mutational analysis of the RET proto-oncogene in 71 Japanese patients with medullary thyroid carcinoma.

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136.

Doray B et al. (1998) Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease.

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137.

Svensson PJ et al. (1998) Low frequency of RET mutations in Hirschsprung disease in Sweden.

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138.

Svensson PJ et al. (1998) Phenotypic variation in a family with mutations in two Hirschsprung-related genes (RET and endothelin receptor B).

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139.

Attié-Bitach T et al. (1998) Expression of the RET proto-oncogene in human embryos.

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140.

NCBI article

NCBI 5979 external link
141.

OMIM.ORG article

Omim 164761 external link
142.

Orphanet article

Orphanet ID 118274 external link
143.

Wikipedia Artikel

Wikipedia DE (Rezeptor-Tyrosinkinase_Ret) external link
Update: 14. August 2020
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