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Article: A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease

TitleA complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease
Authors
Issue Date2020
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosgenetics.org/
Citation
PLoS Genetics, 2020, v. 16, p. article no. e1009106 How to Cite?
AbstractHirschsprung disease (HSCR) is a rare developmental disorder. It leads to the absence of enteric nerve cells (aganglionosis) in the large intestine and is caused by functional defects of neuronal precursor cells during embryonic development of the gut nervous system. The aganglionosis manifests as a variety of symptoms including impaired peristalsis and the formation of a pathogenic dilatation of the intestine (megacolon). The etiology of HSCR is considered to be multifactorial. Variants in more than 20 genes have been reported to be overrepresented in HSCR and replicated in independent cohorts. However, variants in those risk genes account for only 30% of all cases, suggesting that many more genes have to be implicated in the development of HSCR. As the identification and the subsequent validation of novel gene variants to be disease-causing or not, still remains a major challenge, we established and applied a complementary study pipeline. This enabled us to identify four novel candidate genes in two HSCR patients and to validate their potential disease relevance. Our approach represents a suitable way to dissect the complex genetic architecture underlying HSCR. Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and database searches, in silico network analyses, and functional readouts using candidate gene-specific genome-edited cell clones. WES datasets of two patients with HSCR and their non-affected parents were analysed, and four novel HSCR candidate genes could be identified: ATP7A, SREBF1, ABCD1 and PIAS2. Further rare variants in these genes were identified in additional HSCR patients, suggesting disease relevance. Transcriptomics revealed that these genes are expressed in embryonic and fetal gastrointestinal tissues. Knockout of these genes in neuronal cells demonstrated impaired cell differentiation, proliferation and/or survival. Our approach identified and validated candidate HSCR genes and provided further insight into the underlying pathomechanisms of HSCR.
Persistent Identifierhttp://hdl.handle.net/10722/297174
ISSN
2014 Impact Factor: 7.528
2015 SCImago Journal Rankings: 6.308
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMederer, T-
dc.contributor.authorSchmitteckert, S-
dc.contributor.authorVolz, J-
dc.contributor.authorMartinez, C-
dc.contributor.authorRoth, R-
dc.contributor.authorThumberger, T-
dc.contributor.authorEckstein, V-
dc.contributor.authorScheuerer, J-
dc.contributor.authorThoni, C-
dc.contributor.authorLasitschka, F-
dc.contributor.authorCarstensen, L-
dc.contributor.authorGunther, P-
dc.contributor.authorHolland-Cunz, S-
dc.contributor.authorHofstra, R-
dc.contributor.authorBrosens, E-
dc.contributor.authorRosenfeld, JA-
dc.contributor.authorSchaaf, CP-
dc.contributor.authorSchriemer, D-
dc.contributor.authorCeccherini, I-
dc.contributor.authorRusmini, M-
dc.contributor.authorTilghman, J-
dc.contributor.authorLuzon-Toro, B-
dc.contributor.authorTorroglosa, A-
dc.contributor.authorBorrego, S-
dc.contributor.authorTang, CSM-
dc.contributor.authorGarcia-Barcelo, MM-
dc.contributor.authorTam, P-
dc.contributor.authorParamasivam, N-
dc.contributor.authorBewerunge-Hudler, M-
dc.contributor.authorDe La Torre, C-
dc.contributor.authorGretz, N-
dc.contributor.authorRappold, GA-
dc.contributor.authorRomero, P-
dc.contributor.authorNiesler, B-
dc.contributor.authorMcCallion, AS-
dc.date.accessioned2021-03-08T07:15:12Z-
dc.date.available2021-03-08T07:15:12Z-
dc.date.issued2020-
dc.identifier.citationPLoS Genetics, 2020, v. 16, p. article no. e1009106-
dc.identifier.issn1553-7390-
dc.identifier.urihttp://hdl.handle.net/10722/297174-
dc.description.abstractHirschsprung disease (HSCR) is a rare developmental disorder. It leads to the absence of enteric nerve cells (aganglionosis) in the large intestine and is caused by functional defects of neuronal precursor cells during embryonic development of the gut nervous system. The aganglionosis manifests as a variety of symptoms including impaired peristalsis and the formation of a pathogenic dilatation of the intestine (megacolon). The etiology of HSCR is considered to be multifactorial. Variants in more than 20 genes have been reported to be overrepresented in HSCR and replicated in independent cohorts. However, variants in those risk genes account for only 30% of all cases, suggesting that many more genes have to be implicated in the development of HSCR. As the identification and the subsequent validation of novel gene variants to be disease-causing or not, still remains a major challenge, we established and applied a complementary study pipeline. This enabled us to identify four novel candidate genes in two HSCR patients and to validate their potential disease relevance. Our approach represents a suitable way to dissect the complex genetic architecture underlying HSCR. Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and database searches, in silico network analyses, and functional readouts using candidate gene-specific genome-edited cell clones. WES datasets of two patients with HSCR and their non-affected parents were analysed, and four novel HSCR candidate genes could be identified: ATP7A, SREBF1, ABCD1 and PIAS2. Further rare variants in these genes were identified in additional HSCR patients, suggesting disease relevance. Transcriptomics revealed that these genes are expressed in embryonic and fetal gastrointestinal tissues. Knockout of these genes in neuronal cells demonstrated impaired cell differentiation, proliferation and/or survival. Our approach identified and validated candidate HSCR genes and provided further insight into the underlying pathomechanisms of HSCR.-
dc.languageeng-
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosgenetics.org/-
dc.relation.ispartofPLoS Genetics-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleA complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease-
dc.typeArticle-
dc.identifier.emailTang, CSM: claratang@hku.hk-
dc.identifier.emailGarcia-Barcelo, MM: mmgarcia@hku.hk-
dc.identifier.emailTam, P: paultam@hku.hk-
dc.identifier.authorityTang, CSM=rp02105-
dc.identifier.authorityGarcia-Barcelo, MM=rp00445-
dc.identifier.authorityTam, P=rp00060-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pgen.1009106-
dc.identifier.pmid33151932-
dc.identifier.pmcidPMC7643938-
dc.identifier.hkuros321648-
dc.identifier.volume16-
dc.identifier.spagearticle no. e1009106-
dc.identifier.epagearticle no. e1009106-
dc.identifier.isiWOS:000591315700001-
dc.publisher.placeUnited States-

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