Molecular mechanisms of RET‐induced Hirschsprung pathogenesis

  title={Molecular mechanisms of RET‐induced Hirschsprung pathogenesis},
  author={Francesca Lantieri and Paola Griseri and Isabella Ceccherini},
  journal={Annals of Medicine},
  pages={11 - 19}
The RET proto‐oncogene is the major gene involved in the pathogenesis of Hirschsprung (HSCR), a complex genetic disease characterized by lack of ganglia along variable lengths of the gut. Here we present a survey of the different molecular mechanisms through which RET mutations lead to the disease development. Among these, loss of function, gain of function, apoptosis, aberrant splicing and decreased gene expression are exemplified and considered with respect to their pathogenetic impact. In… 
Tissue specific somatic mutations and aganglionosis in Hirschsprung's disease.
Mapping of a Hirschsprung's disease locus in 3p21
A five-marker haplotype, spanning a 118 kb gene-rich region, was found to be overtransmitted to affected offspring and encompasses three genes involved in neurological phenotypes, and could be used in follow-up studies to finally pinpoint this HSCR locus.
Methylation analysis of EDNRB in human colon tissues of Hirschsprung’s disease
It is demonstrated that epigenetic inactivation of the EDNRB gene may play a role in the development of HSCR.
Hirschsprung disease, associated syndromes and genetics: a review
Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment, which stands as a model for genetic disorders with complex patterns of inheritance.
Polymorphisms and expression of the WNT8A gene in Hirschsprung's disease.
The data presented in this study suggest that the WNT8A gene is involved in the susceptibility to HSCR, and plays an important role in the occurrence and development of H SCR.
Whole Exome Sequencing Identifies a Novel Pathogenic RET Variant in Hirschsprung Disease
This is the first study to report the in-frameshift variant p.Phe147del in RET responsible for heritable HSCR, which may function by disrupting the glycosylation of RET protein.
Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma
Although most pheochromocytomas (PCCs) and paragangliomas (PGLs) are sporadic, molecular genetic medicine has revealed that a considerable number of patients with apparently sporadic PCC actually
Expression patterns of dishevelled-2 in different colon tissue segments in Hirschsprung's disease.
The data suggest that the expression of DVL‑2 in colon tissue segments may be important in the pathogenesis of HSCR.
WNT3A gene expression is associated with isolated Hirschsprung disease polymorphism and disease status.
Preliminary results suggest that WNT3A may play an important role in the pathogenesis of HSCR.


Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR).
A role for RET haplotypes containing the -5A promoter variant in the etiology of HSCR is suggested after it was demonstrated that variants of two RET promoter polymorphisms -5G>A and -1C>A from the transcription start site are associated with H SCR.
Molecular heterogeneity of RET loss of function in Hirschsprung's disease.
It is shown that the three mutations caused a loss of function of RET when assayed in two model cell systems, NIH 3T3 and PC12 cells, and the effect of different HSCR mutations was due to different molecular mechanisms.
Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease.
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.
Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease.
The data show that allelic heterogeneity at the RET locus in HSCR is associated with various molecular mechanisms responsible for RET dysfunction.
A single-nucleotide polymorphic variant of the RET proto-oncogene is underrepresented in sporadic Hirschsprung disease
Functional tests were performed which excluded any possible involvement of the C and T alleles in DNA-protein binding, transcript stability and RNA splicing and editing, and found that the T allele is clearly less frequent than in control individuals.
The RET proto‐oncogene induces apoptosis: a novel mechanism for Hirschsprung disease
Results indicate that HSCR may result from apoptosis of RET‐expressing enteric neuroblasts, and it is reported that Hirschsprung‐associated RET mutations impair GDNF control of RET pro‐apoptotic activity.
An intronic nucleotide variant of the RET proto-oncogene causes Hirschsprung disease by interfering with RNA splicing
The association of HSCR with ganglioneuroblastoma in close relatives could be more than coincidental and further investigation into genes driving neural crest differentiation will help to explain the occurrence of different neurocristopathies within the same pedigree.
Frequency of RET mutations in long‐ and short‐segment Hirschsprung disease
The approach of single‐strand conformational polymorphism analysis established for all the 20 exons of the RET proto‐oncogene, and previously used to screen for point mutations in Hirschsprung patients, allowed us to identify seven additional mutations among 39 sporadic and familial cases of HirschSprung disease.
Intrinsic susceptibility to misfolding of a hot-spot for Hirschsprung disease mutations in the ectodomain of RET.
The intrinsic susceptibility to misfolding of mammalian RETECD may be the result of a trade-off that helps to avoid an increased incidence of tumors, at the expense of a greater vulnerability to Hirschsprung disease.
A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk
It is shown that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do.