TY  - JOUR
AU  - Mederer, Tanja
AU  - Schmitteckert, Stefanie
AU  - Volz, Julia
AU  - Martínez, Cristina
AU  - Röth, Ralph
AU  - Thumberger, Thomas
AU  - Eckstein, Volker
AU  - Scheuerer, Jutta
AU  - Thöni, Cornelia
AU  - Lasitschka, Felix
AU  - Carstensen, Leonie
AU  - Günther, Patrick
AU  - Holland-Cunz, Stefan
AU  - Hofstra, Robert
AU  - Brosens, Erwin
AU  - Rosenfeld, Jill A
AU  - Schaaf, Christian P
AU  - Schriemer, Duco
AU  - Ceccherini, Isabella
AU  - Rusmini, Marta
AU  - Tilghman, Joseph
AU  - Luzón-Toro, Berta
AU  - Torroglosa, Ana
AU  - Borrego, Salud
AU  - Sze-Man Tang, Clara
AU  - Garcia-Barceló, Mercè
AU  - Tam, Paul
AU  - Paramasivam, Nagarajan
AU  - Bewerunge-Hudler, Melanie
AU  - De La Torre, Carolina
AU  - Gretz, Norbert
AU  - Rappold, Gudrun A
AU  - Romero, Philipp
AU  - Niesler, Beate
TI  - A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease.
JO  - PLoS Genetics
VL  - 16
IS  - 11
SN  - 1553-7404
CY  - San Francisco, Calif.
PB  - Public Library of Science
M1  - DKFZ-2020-02396
SP  - e1009106 -
PY  - 2020
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.
LB  - PUB:(DE-HGF)16
C6  - pmid:33151932
DO  - DOI:10.1371/journal.pgen.1009106
UR  - https://inrepo02.dkfz.de/record/165816
ER  -