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

English version

Autoři: Tanja Mederer ^aff001; Stefanie Schmitteckert ^aff001; Julia Volz ^aff001; Cristina Martínez ^aff001; Ralph Röth ^aff001; Thomas Thumberger ^aff004; Volker Eckstein ^aff005; Jutta Scheuerer ^aff006; Cornelia Thöni ^aff006; Felix Lasitschka ^aff006; Leonie Carstensen ^aff007; Patrick Günther ^aff007; Stefan Holland-Cunz ^aff008; Robert Hofstra ^aff009; Erwin Brosens ^aff009; Jill A. Rosenfeld ^aff010; Christian P. Schaaf ^aff010; Duco Schriemer ^aff013; Isabella Ceccherini ^aff014; Marta Rusmini ^aff014; Joseph Tilghman ^aff015; Berta Luzón-Toro ^aff016; Ana Torroglosa ^aff016; Salud Borrego ^aff016; Clara Sze-man Tang ^aff018; Mercè Garcia-Barceló ^aff018; Paul Tam ^aff018; Nagarajan Paramasivam ^aff019; Melanie Bewerunge-Hudler ^aff020; Carolina De La Torre ^aff021; Norbert Gretz ^aff021; Gudrun A. Rappold ^aff001; Philipp Romero ^aff007; Beate Niesler ^aff001
Působiště autorů: Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ^aff001; Lleida Institute for Biomedical Research Dr. Pifarré Foundation (IRBLleida), Lleida, Spain ^aff002; nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ^aff003; Centre for Organismal Studies, Heidelberg University, Heidelberg, Germany ^aff004; FACS Core Facility, Campus Heidelberg, Germany ^aff005; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany ^aff006; Pediatric Surgery Division, Heidelberg University Hospital, Heidelberg, Germany ^aff007; Pediatric Surgery, University Children's Hospital, Basel, Switzerland ^aff008; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands ^aff009; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America ^aff010; Baylor Genetics Laboratories, Houston, Texas, United States of America ^aff011; Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany ^aff012; Department of Neuroscience, University Medical Center, Groningen, The Netherlands ^aff013; UOSD Genetica e Genomica delle Malattie Rare, IRCCS, Instituto Giannina Gaslini, Genova, Italy ^aff014; Center for Human Genetics and Genomics, New York University School of Medicine, United States of America ^aff015; Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain ^aff016; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain ^aff017; Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China ^aff018; Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany ^aff019; Genomics and Proteomic Core Facility, German Cancer Research Center, Heidelberg, Germany ^aff020; Center of Medical Research, Medical Faculty Mannheim, Mannheim, Germany ^aff021; Interdisciplinary Center for Neurosciences, University of Heidelberg, Heidelberg, Germany ^aff022
Vyšlo v časopise: A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease. PLoS Genet 16(11): e1009106. doi:10.1371/journal.pgen.1009106
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009106

Souhrn

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.

Klíčová slova:

Cell differentiation – Cloning – Computer-aided drug design – Gene cloning – Gene expression – Hirschsprung disease – Human genetics – Neuronal differentiation

Zdroje

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