ArticleEuropean journal of human genetics : EJHG2016
RET and EDNRB mutation screening in patients with Hirschsprung disease: Functional studies and its implications for genetic counseling.
Article in European journal of human genetics : EJHG, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 19 citations in OpenAlex.
- High incidence of EDNRB gene mutation in seven southern Chinese familial cases with Hirschsprung's disease.Pediatric surgery international · 2024Article
- Circular RNA MTCL1 targets SMAD3 by sponging miR-145-5p for regulation of cell proliferation and migration in Hirschsprung's disease.Pediatric surgery international · 2023Article
- Novel CausativeJournal of pediatric genetics · 2022Article
- Deviation from baseline mutation burden provides powerful and robust rare-variants association test for complex diseases.Nucleic acids research · 2022Article
- Review
- GermlineFrontiers in endocrinology · 2021Article
- Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated Hypercalcemia.Hormones & cancer · 2020Article
- Sequence characterization of RET in 117 Chinese Hirschsprung disease families identifies a large burden of de novo and parental mosaic mutations.Orphanet journal of rare diseases · 2019Article
- Functional Studies on NovelFrontiers in genetics · 2019Article
- Advances in understanding functional variations in the Hirschsprung disease spectrum (variant Hirschsprung disease).Pediatric surgery international · 2017Review
- A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity.PLoS genetics · 2016Article
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hirschsprung disease (HSCR) is a major cause of chronic constipation in children. HSCR can be caused by germline mutations in RET and EDNRB. Defining causality of the mutations identified is difficult and almost exclusively based on in silico predictions. Therefore, the reported frequency of pathogenic mutations might be overestimated. We combined mutation analysis with functional assays to determine the frequencies of proven pathogenic RET and EDNRB mutations in HSCR. We sequenced RET and EDNRB in 57 HSCR patients. The identified RET-coding variants were introduced into RET constructs and these were transfected into HEK293 cells to determine RET phosphorylation and activation via ERK. An exon trap experiment was performed to check a possible splice-site mutation. We identified eight rare RET-coding variants, one possible splice-site variant, but no rare EDNRB variants. Western blotting showed that three coding variants p.(Pr270Leu), p.(Ala756Val) and p.(Tyr1062Cys) resulted in lower activation of RET. Moreover, only two RET variants (p.(Ala756Val) and p.(Tyr1062Cys)) resulted in reduced ERK activation. Splice-site assays on c.1880-11A>G could not confirm its pathogenicity. Our data suggest that indeed almost half of the identified rare variants are proven pathogenic and that, hence, functional studies are essential for proper genetic counseling.
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