Human Homology and Candidate Genes for theDominant megacolonLocus, a Mouse Model of Hirschsprung Disease

Pingault, Véronique; Puliti, Aldamaria; Prehu, Marie-Odette; Samadi, Abbas; Bondurand, Nadège; Goossens, Michel

doi:10.1006/geno.1996.4476

Cited by 29 publications

(11 citation statements)

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“…To finish with this group of genes, we should highlight DRG1 which maps to 22q12^q13.1 region 30 . It has been shown in humans that this locus is a susceptibility region for HSCR 31 . DRG1 encodes for a GTPase highly expressed during CNS embryogenesis 32 .…”

Section: Discussionmentioning

confidence: 99%

Overexpression of DNMT3b target genes during Enteric Nervous System development contribute to the onset of Hirschsprung disease

Villalba‐Benito

Torroglosa

Fernández

et al. 2017

Sci Rep

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Hirschsprung disease (HSCR) is attributed to a failure of neural crest cells (NCCs) to migrate, proliferate, differentiate and/or survive in the bowel wall during embryonic Enteric Nervous System (ENS) development. ENS formation is the result from a specific gene expression pattern regulated by epigenetic events, such DNA methylation by the DNA methyltransferases (DNMTs), among other mechanisms. Specifically, DNMT3b de novo methyltransferase is associated with NCCs development and has been shown to be implicated in ENS formation and in HSCR. Aiming to elucidate the specific mechanism underlying the DNMT3b role in such processes, we have performed a chromatin immunoprecipitation coupled with massively parallel sequencing analysis to identify the DNMT3B target genes in enteric precursor cells (EPCs) from mice. Moreover, the expression patterns of those target genes have been analyzed in human EPCs from HSCR patients in comparison with controls. Additionally, we have carried out a search of rare variants in those genes in a HSCR series. Through this approach we found 9 genes showing a significantly different expression level in both groups. Therefore, those genes may have a role in the proper human ENS formation and a failure in their expression pattern might contribute to this pathology.

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Section: Discussionmentioning

confidence: 99%

Overexpression of DNMT3b target genes during Enteric Nervous System development contribute to the onset of Hirschsprung disease

Villalba‐Benito

Torroglosa

Fernández

et al. 2017

Sci Rep

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“…However, a mutation in GDNF itself was neither necessary nor sufficient to cause HSCR (35,36), because major defects in the Ret pathway would be embryonic lethal or roles of GDNF in enteric neurogenesis could be compensated for by other neurotrophic factors, for example, neurturin. The analysis of another HSCR model mouse, the Dominant megacolon (Dom), might introduce a novel susceptibility gene that lies in human chromosome 22q12-q13 (37).…”

Section: Discussionmentioning

confidence: 99%

Novel Mutations of the Endothelin B Receptor Gene in Patients with Hirschsprung's Disease and Their Characterization

Tanaka¹,

Moroi²,

Iwai³

et al. 1998

Journal of Biological Chemistry

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Hirschsprung's disease (HSCR) is a congenital intestinal disease, characterized by the absence of ganglion cells in the distal portion of the intestinal tract. Recently, three susceptibility genes have been identified in HSCR, namely the RET protooncogene, the endothelin B (ET B ) receptor gene (EDNRB), and the endothelin-3 (ET-3) gene (EDN3). To investigate whether mutations in EDNRB could be related with HSCR in non-inbred populations in Japan, we examined alterations of the gene in 31 isolated patients. Three novel mutations were detected as follows: two transversions, A to T and C to A at nucleotides 311 (N104I) and 1170 (S390R), respectively, and a transition, T to C at nucleotide 325 (C109R). To analyze functions of these mutant receptors, they were expressed in Chinese hamster ovary cells. S390R mutation did not change the binding affinities but caused the decreases in the ligand-induced increment of intracellular calcium and in the inhibition of adenylyl cyclase activity, showing the impairment of the intracellular signaling. C109R receptors were proved to be localized near the nuclei as an unusual 44-kDa protein with the extremely low affinity to endothelin-1 (ET-1) and not to be translocated into the plasma membrane. On the other hand, N104I receptors showed almost the same binding affinities and functional properties as those of the wild type. Therefore, we conclude that S390R and C109R mutations could cause HSCR but that N104I mutation might be polymorphous. Hirschsprung's disease (HSCR)1 is a congenital intestinal disorder, characterized by the absence of ganglion cells in the distal portion of the intestinal tract, as a consequence of premature arrest of cranio-caudal migration of neural crest cells. Recently, three susceptibility genes have been identified in HSCR, namely the RET protooncogene, the endothelin B (ET B ) receptor gene (EDNRB), and the endothelin-3 (ET-3) gene (EDN3).Mice with targeted null disruption of Ret exhibited an autosomal recessive phenotype comprising the total lack of the enteric nervous system and renal agenesis (1), that provided an excellent model of HSCR. Approximately 50 mutations in RET have so far been identified, and the RET mutations account for 50% of familial and 15-20% of sporadic cases of HSCR, over 75% of which are associated with long segment HSCR (2-6).Endothelins (ETs) are a family of 21 amino acid vasoactive peptides, consisting of three isopeptides, ET-1, ET-2 and ET-3, that act on G protein-coupled receptors, ET A and ET B (7-11). ET A exhibits different affinities to the three isopeptides in the order of ET-1 Ն ET-2 Ͼ Ͼ ET-3. ET B accepts all three isopeptides equally. These receptors regulate multiple effector pathways, for example, phospholipase C via G q , and adenylyl cyclase via G s in smooth muscle cells (ET A ), and via G i in endothelial cells (ET B ) (12, 13). Mice with targeted null disruption of either Ednrb or Edn3 exhibit an identical phenotype, coat color spotting, and aganglionic megacolon, similar to HSCR or Shah-Waardenburg syndrome in...

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“…The reported incidence of genito-urinary anomalies also shows considerable variation [3,7,13,18,37,60,61] and they are of particular interest as they are commonly identified in the ret knockout mouse model [62]. Certain HSCR-associated syndromes (e.g.…”

Section: Intestinal Atresiamentioning

confidence: 98%

The contribution of associated congenital anomalies in understanding Hirschsprung’s disease

Moore

2006

Ped Surgery Int

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Hirschsprung's disease (HSCR) is a complex congenital disorder which, from a molecular perspective, appears to result due to disruption of normal signalling during development of enteric nerve cells, resulting in aganglionosis of the distal bowel. Associated congenital anomalies occur in at least 5-32% (mean 21%) of patients and certain syndromic phenotypes have been linked to distinct genetic sites, indicating underlying genetic associations of the disease and probable gene-gene interaction in its pathogenesis. Clear-cut associations with HSCR include Down's syndrome, dominant sensorineural deafness, Waardenburg syndrome, neurofibromatosis, neuroblastoma, phaeochromocytoma, the MEN type IIB syndrome and other abnormalities. Individual anomalies vary from 2.97% to 8%, the most frequent being the gastrointestinal tract (GIT) (8.05%), the central nervous system (CNS) and sensorineural anomalies (6.79%) and the genito-urinary tract (6.05%). Other associated systems include the musculoskeletal (5.12%), cardiovascular systems (4.99%), craniofacial and eye abnormalities (3%) and less frequently the skin and integumentary system (ectodermal dysplasia) and syndromes related to cholesterol and fat metabolism. In addition to associations with neuroblastoma and tumours related to MEN2B, HSCR may also be associated with tumours of neural origin such as ganglioneuroma, ganglioneuroblastoma, retinoblastoma and tumours associated with neurofibromatosis and other autonomic nervous system disturbances. The contribution of the major susceptibility genes on chromosome 10 (RET) and chromosome 13 (EDNRB) is well established in the phenotypic expression of HSCR. Whereas major RET mutations may result in HSCR by haploinsufficiency in 20-25% of cases, the etiology of the majority of sporadic HSCR is not as clear, appearing to arise from the combined cumulative effects of susceptibility loci at critical genes controlling the mechanisms of cell proliferation, differentiation and maturation. In addition, potential "modifying" associations exist with chromosome 2, 9, 20, 21 and 22, and we explore the importance of certain flanking genes of critical areas in the final phenotypic expression of HSCR.

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Human Homology and Candidate Genes for theDominant megacolonLocus, a Mouse Model of Hirschsprung Disease

Cited by 29 publications

References 4 publications

Overexpression of DNMT3b target genes during Enteric Nervous System development contribute to the onset of Hirschsprung disease

Overexpression of DNMT3b target genes during Enteric Nervous System development contribute to the onset of Hirschsprung disease

Novel Mutations of the Endothelin B Receptor Gene in Patients with Hirschsprung's Disease and Their Characterization

The contribution of associated congenital anomalies in understanding Hirschsprung’s disease

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