RT Journal Article
T1 A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease.
A1 Mederer, Tanja
A1 Schmitteckert, Stefanie
A1 Volz, Julia
A1 Martinez, Cristina
A1 Röth, Ralph
A1 Thumberger, Thomas
A1 Eckstein, Volker
A1 Scheuerer, Jutta
A1 Thöni, Cornelia
A1 Lasitschka, Felix
A1 Carstensen, Leonie
A1 Günther, Patrick
A1 Holland-Cunz, Stefan
A1 Hofstra, Robert
A1 Brosens, Erwin
A1 Rosenfeld, Jill A
A1 Schaaf, Christian P
A1 Schriemer, Duco
A1 Ceccherini, Isabella
A1 Rusmini, Marta
A1 Tilghman, Joseph
A1 Luzón-Toro, Berta
A1 Torroglosa, Ana
A1 Borrego, Salud
A1 Sze-Man Tang, Clara
A1 Garcia-Barcelo, Merce
A1 Tam, Paul
A1 Paramasivam, Nagarajan
A1 Bewerunge-Hudler, Melanie
A1 De-La-Torre, Carolina
A1 Gretz, Norbert
A1 Rappold, Gudrun A
A1 Romero, Philipp
A1 Niesler, Beate
K1 Cell Differentiation
K1 Cell Line
K1 Computer Simulation
K1 Disease Models, Animal
K1 Gene Expression Profiling
K1 Hirschsprung Disease
K1 Infant
K1 Mice
K1 Exome Sequencing
AB 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.
PB Public Library of Science
YR 2020
FD 2020-11-05
LK http://hdl.handle.net/10668/16550
UL http://hdl.handle.net/10668/16550
LA en
NO Mederer T, Schmitteckert S, Volz J, Martínez C, Röth R, Thumberger T, et al. A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease. PLoS Genet. 2020 Nov 5;16(11):e1009106.
DS RISalud
RD Oct 24, 2025