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RET overactivation leads to concurrent Hirschsprung disease and intestinal ganglioneuromas.

ABSTRACT: Appropriately balanced RET signaling is of crucial importance during embryonic neural crest cell migration, proliferation and differentiation. RET deficiency, for example, leads to intestinal aganglionosis (Hirschsprung disease), whereas overactive RET can lead to multiple endocrine neoplasia (MEN) syndromes. Some RET mutations are associated with both intestinal aganglionosis and MEN-associated tumors. This seemingly paradoxical occurrence has led to speculation of a 'Janus mutation' in RET that causes overactivation or impairment of RET activity depending on the cellular context. Using an intestinal catenary culture system to test the effects of GDNF-mediated RET activation, we demonstrate the concurrent development of distal colonic aganglionosis and intestinal ganglioneuromas. Interestingly, the tumors induced by GDNF stimulation contain enteric neuronal progenitors capable of reconstituting an enteric nervous system when transplanted into a normal developmental environment. These results suggest that a Janus mutation may not be required to explain co-existing Hirschsprung disease and MEN-associated tumors, but rather that RET overstimulation alone is enough to cause both phenotypes. The results also suggest that reprogramming tumor cells toward non-pathological fates may represent a possible therapeutic avenue for MEN-associated neoplasms.

SUBMITTER: Nagy N

PROVIDER: S-EPMC7657479 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Identifying candidate Hirschsprung disease-associated RET variants.

Project description:Patients with sporadic Hirschsprung disease (HSCR) show increased allele sharing at markers in the 5' region of the RET locus, indicating the presence of a common ancestral RET mutation. In a previous study, we found a haplotype of six SNPs that was transmitted to 55.6% of our patients, whereas it was present in only 16.2% of the controls we used. Among the patients with that haplotype, 90.8% had it on both chromosomes, which led to a much higher risk of developing HSCR than when the haplotype occurred heterozygously. To more precisely define the HSCR-associated region and to identify candidate disease-associated variant(s), we sequenced the shared common haplotype region from 10 kb upstream of the RET gene through intron 1 and exon 2 (in total, 33 kb) in a patient homozygous for the common risk haplotype and in a control individual homozygous for the most common nonrisk haplotype. A comparison of these sequences revealed 86 sequence differences. Of these 86 variations, 8 proved to be in regions highly conserved among different vertebrates and within putative transcription factor binding sites. We therefore considered these as candidate disease-associated variants. Subsequent genotyping of these eight variants revealed a strong disease association for six of the eight markers. These six markers also showed the largest distortions in allele transmission. Interspecies comparison showed that only one of the six variations was located in a region also conserved in a nonmammalian species, making it the most likely candidate HSCR-associated variant.

| S-EPMC1199373 | biostudies-literature

RET somatic mutations are underrecognized in Hirschsprung disease.

Project description:PurposeWe aimed to determine the frequency of RET mosaicism in Hirschsprung disease (HSCR), test whether it has been underestimated, and to assess its contribution to HSCR risk.MethodsTargeted exome sequencing (n = 83) and RET single-gene screening (n = 69) were performed. Amplicon-based deep sequencing was applied on multiple tissue samples. TA cloning and sequencing were conducted for validation.ResultsWe identified eight de novo mutations in 152 patients (5.2%), of which six were pathogenic mosaic mutations. Two of these patients were somatic mosaics, with mutations detected in blood, colon, and saliva (mutant allele frequency: 35-44%). In addition, germ-line mosaicism was identified in four clinically unaffected subjects, each with an affected child, in multiple tissues (mutant allele frequency: 1-28%).ConclusionSomatic mutations of the RET gene are underrecognized in HSCR. Molecular investigation of the parents of patients with seemingly sporadic mutations is essential to determine recurrence risk in these families.

| S-EPMC7814876 | biostudies-literature

c-Ret-mediated hearing loss in mice with Hirschsprung disease.

Project description:A significantly increased risk for dominant sensorineural deafness in patients who have Hirschsprung disease (HSCR) caused by endothelin receptor type B and SOX10 has been reported. Despite the fact that c-RET is the most frequent causal gene of HSCR, it has not been determined whether impairments of c-Ret and c-RET cause congenital deafness in mice and humans. Here, we show that impaired phosphorylation of c-Ret at tyrosine 1062 causes HSCR-linked syndromic congenital deafness in c-Ret knockin (KI) mice. The deafness involves neurodegeneration of spiral ganglion neurons (SGNs) with not only impaired phosphorylation of Akt and NF-kappaB but decreased expression of calbindin D28k in inner ears. The congenital deafness involving neurodegeneration of SGNs in c-Ret KI mice was rescued by introducing constitutively activated RET. Taken together with our results for three patients with congenital deafness with c-RET-mediated severe HSCR, our results indicate that c-Ret and c-RET are a deafness-related molecule in mice and humans.

| S-EPMC2919946 | biostudies-literature

Exclusion of RET and Pax 3 loci in Waardenburg-Hirschsprung disease.

Project description:The RET and the Pax 3 genes have recently been shown to account for autosomal dominant Hirschsprung's disease (HSCR) and Waardenburg syndrome type 1 (WS1) respectively, which led us to consider them as candidate genes in the WS/HSCR association. Linkage analyses performed in a consanguineous WS/HSCR family support the view that neither the RET locus nor the Pax 3 locus are involved in the disease phenotype. Hence, at least one further locus altering neural crest cell development is responsible for the pleiotropic features observed in the WS/HSCR association.

| S-EPMC1050384 | biostudies-other

A gene regulatory network explains RET-EDNRB epistasis in Hirschsprung disease.

Project description:Disruptions in gene regulatory networks (GRNs), driven by multiple deleterious variants, potentially underlie complex traits and diseases. Hirschsprung disease (HSCR), a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. We previously demonstrated that RET transcription in the ENS is controlled by an extensive GRN involving the transcription factors (TFs) RARB, GATA2 and SOX10 and other HSCR genes. We now demonstrate, using human and mouse cellular and animal models, that EDNRB is transcriptionally regulated in the ENS by GATA2, SOX10 and NKX2.5 TFs. Significantly, RET and EDNRB expression is regulated by their shared use of GATA2 and SOX10, and in turn, these TFs are controlled by EDNRB and RET in a dose-dependent manner. This study expands the ENS development GRN to include both RET and EDNRB, uncovers the mechanistic basis for RET-EDNRB epistasis and emphasizes how functionally different genes associated with a complex disorder can be united through a common GRN.

| S-EPMC7275776 | biostudies-literature

AB099. Joint effects of RET and SEMA3 polymorphisms in Hirschsprung disease

Project description:Background RET and Semaphorin 3 (SEMA3) common variants have been associated with Hirschsprung disease (HSCR), but their genetic interactions for development of HSCR is not established yet. To determine the joint effects of RET gene, rs2435357, and SEMA3 gene with three markers; rs1583147, rs12707682, and rs11766001 polymorphisms in Indonesian HSCR patients. Methods Sixty HSCR patients and 115 non-HSCR controls were included in this study. Four genetic markers of the RET and SEMA3 were examined in 175 DNAs using TaqMan Genotyping assay. Case-control analysis and transmission disequilibrium test (TDT) were used to determine an association between four genetic markers and HSCR. We used a P value of <0.013 for a significant association. Results There was a strong association between RET rs2435357 marker and HSCR either by case-control analysis (OR =4.46, P=2.5×10?8) or TDT (P=4.2×10?6), but not SEMA3 rs1583147 (OR =1.9, P=0.023 and P=0.11, respectively) and rs12707682 (OR =1.5, P=0.06 and P=0.041, respectively). Two locus analyses of variants revealed that RET rs2435357 (TT), in combination with SEMA3 rs1583147 (CT) or rs12707682 (CC), were associated with the augmented disease risks of HSCR (OR =2.88, P=0.016 and OR =19.9, P=0.005, respectively) compared with a single variant of SEMA3 rs1583147 or rs12707682. Moreover, the SEMA3 rs11766001 frequencies in HSCR patients and non-HSCR subjects were 1.7% and 0.8% (P=0.48), respectively. Conclusions The genetic effects of SEMA3 genotypes are epistatic to RET. The rarity of SEMA3 rs11766001 in Indonesia could be explained by the founder effect.

| S-EPMC5641808 | biostudies-literature

AB097. Combined effects of RET transcriptional enhancer variants in Hirschsprung disease

Project description:Background Hirschsprung disease (HSCR) is a complex genetic disorder, which characterized by absence of ganglion cells along variable lengths of the intestines in neonates, with the RET was identified as a major locus involved in HSCR. In this study, we investigated the joint effects of common variants within the RET transcriptional enhancer, rs2435357 and rs2506030, for development of HSCR in Indonesia. Methods Sixty HSCR patients and 122 non-HSCR controls was involved in this study. Two genetic markers of the RET were examined using TaqMan assay. We analyzed the case-control association tests between two genetic markers and HSCR using the statistic. A P value <0.025 is considered significant given that two tests (markers) were performed in the analysis. Results There was high correlation between RET rs2435357 marker and HSCR either by case-control analysis (OR =4.46, P=2.5×10?8) or transmission disequilibrium test (TDT, P=4.2×10?6), but not RET rs2506030 (OR =1.68, P=0.042 and P=0.034, respectively). Two locus analyses of variants revealed that RET rs2435357 (TT), in combination with rs2506030 (GG), were associated with the increased disease risks of HSCR (OR =5.42, P=3.9×10?6) compared with a single variant of rs2506030. Conclusions Our study shows that RET rs2435357 variant is a strong genetic risk factors for development of HSCR in Indonesia. In addition, the disease effects of RET rs2506030 genotypes are crucially dependent on the effects of rs2435357 genotypes.

| S-EPMC5641765 | biostudies-literature

RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients.

Project description:Rare (RVs) and common variants of the RET gene contribute to Hirschsprung disease (HSCR; congenital aganglionosis). While RET common variants are strongly associated with the commonest manifestation of the disease (males; short-segment aganglionosis; sporadic), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females; long/total colonic aganglionosis; familial).Here we present the screening for RVs in the RET CDS and intron/exon boundaries of 601 Chinese HSCR patients, the largest number of patients ever reported. We identified 61 different heterozygous RVs (50 novel) distributed among 100 patients (16.64%). Those include 14 silent, 29 missense, 5 nonsense, 4 frame-shifts, and one in-frame amino-acid deletion in the CDS, two splice-site deletions, 4 nucleotide substitutions and a 22-bp deletion in the intron/exon boundaries and 1 single-nucleotide substitution in the 5' untranslated region. Exonic variants were mainly clustered in RET the extracellular domain. RET RVs were more frequent among patients with the most severe phenotype (24% vs. 15% in short-HSCR). Phasing RVs with the RET HSCR-associated haplotype suggests that RVs do not underlie the undisputable association of RET common variants with HSCR. None of the variants were found in 250 Chinese controls.

| S-EPMC3235168 | biostudies-literature

Whole Exome Sequencing Identifies a Novel Pathogenic RET Variant in Hirschsprung Disease.

Project description:Hirschsprung disease is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract. To uncover genetic variants contributing to HSCR, we performed whole exome sequencing on seven members of an HSCR family. With the minor allele frequency (MAF) calculated by gnomAD, we finally filtered a total of 1,059 rare variants in this family (MAF < 0.1%). With the mode of inheritance and pathogenicity scores by bioinformatics tools, we identified an in-frameshift variant p.Phe147del in RET as the disease-causing variant. Further analysis revealed that the in-frameshift variant may function by disrupting the glycosylation of RET protein. To our knowledge, this is the first study to report the in-frameshift variant p.Phe147del in RET responsible for heritable HSCR.

| S-EPMC6339922 | biostudies-literature

Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease.

Project description:BackgroundHirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract in neonates. Three polymorphisms, rs2435357, within a conserved transcriptional enhancer of RET, and, rs7835688 and rs16879552, within intron 1 of NRG1, have been shown to be associated with isolated forms of HSCR. We wished to replicate these findings, and study the interactions between these variants, in Indonesian HSCR patients.MethodsSixty isolated HSCR patients and 124 controls were ascertained for this study. The three genetic markers were examined using TaqMan Genotyping Assays in genomic DNA for association studies.ResultsRET rs2435357 showed the strongest association with HSCR both by case-control analysis (p=2.5 × 10(-8)) and transmission disequilibrium test (p=4.2 × 10(-6)). NRG1 rs7835688 was modestly associated with HSCR only by case-control analysis (p=4.3 × 10(-3)), whereas rs16879552 demonstrated no association (p>0.097). Two locus analyses of variants showed significant interactions with increased and decreased disease risks of HSCR at NRG1 but conditional on rs2435357 genotype.ConclusionsRET and NRG1 variants are common susceptibility factors for HSCR in Indonesia. These common variants demonstrate that development of HSCR requires joint effects of RET and NRG1 early in gut development.

| S-EPMC4258000 | biostudies-literature

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