Mechanism of ret dysfunction by Hirschsprung mutations affecting its extracellular domain.

@article{Iwashita1996MechanismOR,
  title={Mechanism of ret dysfunction by Hirschsprung mutations affecting its extracellular domain.},
  author={Toshihide Iwashita and Hideki Murakami and Naoya Asai and Masahide Takahashi},
  journal={Human molecular genetics},
  year={1996},
  volume={5 10},
  pages={
          1577-80
        }
}
Hirschsprung disease (HSCR) is a congenital disorder associated with the absence of intrinsic ganglion cells in the distal gastrointestinal tract. Recently, many missense, nonsense and frameshift mutations of the ret proto-oncogene were found in familial and sporadic cases of HSCR. Consistent with the view that the HSCR phenotype is the result of inactivation of Ret, the missense mutations detected in the tyrosine kinase domain were demonstrated to result in a marked decrease of the kinase… 
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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The genetic findings in a novel family with multiple endocrine neoplasia type 2 are reported: a specific RET haplotype was documented in patients with Hirschsprung disease associated with medullary thyroid carcinoma, but it was absent in patientsWith only medullARY thyroid carcinomas.
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References

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TLDR
The data suggest a loss of function effect of HSCR mutations which might act through a dominant negative mechanism in the RET/PTC2 chimaeric oncogene which is capable of transforming NIH3T3 mouse fibroblasts and of differentiating pC12 rat pheochromocytoma cells.
Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease
TLDR
The hypothesis that RET, in addition to its potential role in tumorigenesis, plays a critical role in the embryogenesis of the mammalian enteric nervous system is supported.
Mutations of the RET proto-oncogene in Hirschsprung's disease
TLDR
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, and it is shown that the mutant genotypes segregate with the disease in HSCR families.
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TLDR
The data suggest that the overall frequency of RET mutations in HSCR patients is low and therefore, other genetic and/or environmental determinants contribute to the majority of HscR susceptibility, and at present, there is no obvious relationship between RET genotype and H SCR phenotype.
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TLDR
The low penetrance of the mutant gene, the lack of genotype-phenotype correlation, the sex-dependent effect of RET mutations and the variable clinical expression of the disease support the existence of one or more modifier genes in familial HSCR.
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TLDR
Observations indicate that dysfunction or loss of function of endothelin-B receptor may be involved in the aetiology of some isolated patients with HSCR.
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TLDR
Heterozygous EDNRB missense mutations are reported in isolated HSCR, giving further support to the role of the endothelin-signalling pathway in the development of neural crest-derived enteric neurons and suggesting that EDNRBs could be dosage sensitive.
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TLDR
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Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population.
TLDR
DNA samples from 17 probands of Italian origin with HSCR are analysed and two novel EDNRB mutations are identified, confirming the involvement ofEDNRB in HSCRs pathogenesis and demonstrating that EDNRBs mutations could contribute to HSCr disease in non-inbred populations.
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