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

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): e32767. doi:10.1371/journal.pgen.1009106
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009106


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


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