Molekulargenetische Diagnostik
Praxis Dr. Mato Nagel

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.

Diagnostik:

Clinic Untersuchungsmethoden Familienuntersuchung
Bearbeitungszeit 5
Probentyp genomic DNA
Clinic Untersuchungsmethoden Multiplex ligationsabhängige Amplifikation
Bearbeitungszeit 25
Probentyp genomic DNA
Clinic Untersuchungsmethoden Direkte Sequenzierung der proteinkodierenden Bereiche eines Gens
Bearbeitungszeit 25
Probentyp genomic DNA
Clinic Untersuchungsmethoden Hochdurchsatz-Sequenzierung
Bearbeitungszeit 25
Probentyp genomic DNA

Krankheiten:

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

Referenzen:

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2.

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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.

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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.

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7.

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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8.

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9.

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

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10.

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11.

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12.

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13.

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18.

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20.

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30.

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34.

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35.

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36.

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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37.

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38.

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39.

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40.

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41.

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42.

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43.

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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44.

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45.

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46.

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47.

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48.

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49.

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50.

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51.

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52.

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54.

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55.

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56.

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57.

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58.

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59.

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60.

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61.

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62.

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63.

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

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64.

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65.

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66.

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67.

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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68.

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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69.

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70.

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71.

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72.

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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73.

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74.

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75.

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76.

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77.

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78.

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79.

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

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80.

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81.

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82.

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83.

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84.

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85.

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86.

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87.

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88.

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89.

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94.

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95.

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96.

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97.

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98.

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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99.

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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100.

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101.

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104.

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108.

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109.

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110.

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111.

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112.

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113.

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114.

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115.

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116.

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117.

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118.

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120.

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121.

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122.

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124.

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125.

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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126.

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

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127.

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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128.

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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129.

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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130.

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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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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