Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease

@article{Romeo1994PointMA,
  title={Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease},
  author={Giovanni Romeo and P. Ronchetto and Yin Luo and Virginia Barone and Marco Seri and Isabella Ceccherini and Barbara Pasini and Renata Bocciardi and Margherita Lerone and Helena A K{\"a}{\"a}ri{\"a}inen and Giuseppe Martucciello},
  journal={Nature},
  year={1994},
  volume={367},
  pages={377-378}
}
HIRSCHSPRUNG'S disease is a genetic disorder of neural crest development affecting 1 in 5,000 births. It is characterized by the absence of intramural ganglion cells in the hindgut, which often results in partial to complete intestinal obstruction during the first years of life. An autosomal dominant gene causing this disease was recently mapped to chromosome 10q11.2 (refs 1, 2), using an interstitial deletion of this region isolated in a cell hybrid3,4. It was subsequently localized to a 250… 
Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease.
TLDR
The data show that allelic heterogeneity at the RET locus in HSCR is associated with various molecular mechanisms responsible for RET dysfunction.
Mechanism of ret dysfunction by Hirschsprung mutations affecting its extracellular domain.
TLDR
Five mutations in the extracellular domain examined inhibit transport of the ret proto-oncogene protein to the plasma membrane, and significantly decreased the transforming activity of Ret with multiple endocrine neoplasia (MEN) 2A mutation for which cell surface expression is required.
Mutations in the Extracellular Domain Cause RET Loss of Function by a Dominant Negative Mechanism
TLDR
The results suggest that HSCR mutations in the extracellular region cause RET loss of function through a dominant negative mechanism.
Functional analysis of RET with Hirschsprung mutations affecting its kinase domain.
TLDR
Hirschsprung disease can result from these distant functional classes of kinase domain mutation of RET, which severely impaired the phospholipase C-gamma signaling pathway in SK-N-MC cells.
Mutation of RET proto-oncogene in Hirschsprung's disease and intestinal neuronal dysplasia.
TLDR
The frequency of RET proto-oncogene mutation is quite different between IND and HD in Chinese population and IND is a distinct clinical entity genetically different from HD.
Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes and Hirschsprung disease
TLDR
The observation that the major tissues affected in MEN 2 and Hirschsprung disease have a common origin in the embryonal neural crest, suggest that RET encodes a receptor for a developmental regulator involved in the genesis of a variety of neural crest derivatives, and in the organogenesis of the kidney.
A homozygous missense mutation in the tyrosine kinase domain of the RET proto-oncogene in an infant with total intestinal aganglionosis
TLDR
The homozygous RET mutation seemed to cause a critical alteration of the Ret tyrosine kinase activity, which resulted in total intestinal aganglionosis but not renal agenesis, suggesting differing threshold values for RET signal transduction in species or organs.
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References

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Close linkage with the RET protooncogene and boundaries of deletion mutations in autosomal dominant Hirschsprung disease.
TLDR
The pentagastrin test (which detects preclinical forms of MEN 2A or B) is negative in adult HSCR patients with deletions of the RET gene, which represents a good candidate for the search of mutations causing H SCR.
Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A
TLDR
This work has identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls, and found that 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of theRET extracellular and transmembrane domains.
Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.
TLDR
Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders.
A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10
TLDR
Hirschsprung disease is a frequent congenital disorder of unknown origin characterized by the absence of parasympathetic intrinsic ganglion cells of the hindgut, suggesting that a dominant gene for HSCR maps to 10q11.2, a region to which other neural crest defects have been mapped.
A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma
TLDR
It is shown that MEN 2B is also associated with mutation of the RET proto-oncogene, and a mutation in codon 664, causing the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein, was found in all nine unrelated men 2B patients studied.
Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A
TLDR
The in vivo activation of ret in human papillary thyroid carcinomas is provided by the fusion of its tyrosine kinase domain with different genes and can be mediated by different mechanisms of gene rearrangement.
Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret
TLDR
It is shown that mice homozygous for a targeted mutation in c-ret develop to term, but die soon after birth, showing renal agenesis or severe dysgenesis, and lacking enteric neurons throughout the digestive tract, indicating an essential component of a signalling pathway required for renal organogenesis and enteric neurogenesis.
A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10
TLDR
Linkage in a subset of five HSCR families to the pericentromeric region of chromosome 10 is identified, thereby proving monogenic inheritance in some families, and localize this gene to a region of ≈7 centiMorgans, in close proximity to the locus for multiple endocrine neoplasia type 2 (MEN2).
Deleted and normal chromosome 10 homologs from a patient with Hirschsprung disease isolated in two cell hybrids through enrichment by immunomagnetic selection.
TLDR
A cytogenetically undetectable deletion was observed in a patient with total colonic aganglionosis with small bowel involvement (TCSA), a variant of Hirschsprung disease, and it is hypothesized that they originate from mutations in different genes clustered in the centromeric region of 10q.
Deletion of the c-kit protooncogene in the human developmental defect piebald trait.
TLDR
The demonstration of a genomic c-Kit deletion in one subject with piebald trait and the marked concordance of the human and mouse phenotypes provide strong evidence for the role of c-kit in the development of human melanocytes and in the pathogenesis of pieb Bald trait.
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