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Dissertation Abstract I Dissertation submitted to the Combined Faculty of Natural Sciences and Mathematics of the Ruperto Carola University Heidelberg, Germany for the degree of Doctor of Natural Sciences Presented by M.Sc. Tanja Mederer born in: Darmstadt, Germany Oral examination: 8.10.2019 II Abstract Abstract III Identification and characterization of novel candidate genes for Hirschsprung’s disease – a developmental disorder of the enteric nervous system Referees: Prof. Dr. Gudrun Rappold Prof. Dr. Beate Niesler IV Abstract Abstract I ABSTRACT The neurodevelopmental disorder Hirschsprung’s disease (HSCR) represents the most common cause for congenital obstruction and is characterized by a lack of enteric neurons (aganglionosis) in distinct segments of the colon. This aganglionosis is caused by dysfunctions in the neural crest cell (NCC) population which is responsible for enteric nervous system (ENS) generation during embryogenesis. Specifically, either proliferation, migration, differentiation or cell survival of NCC-derived progenitor cells is impaired. The main symptom of this disorder is represented by a megacolon formation. Patients are routinely treated by surgical resections of the aganglionic segment, but gastrointestinal impairments may persist in a fraction of patients even life-long. HSCR is classified as rare and multifactorial disorder. Up to now more than 20 genes are classified as validated disease-causing loci, including the major susceptibility locus RET, but many more genetic factors have been implicated in the pathoaetiology. However, in the majority of patients the genetic disease causes are still unknown. Next-generation sequencing technologies provide the possibility to rapidly uncover the individual’s genetic architecture. Nevertheless, dissecting the genetic findings of importance and correlating them with the pathomechanisms is a major challenge especially in complex diseases as HSCR. This study aimed to establish a complementary research approach for identification and characterization of novel HSCR candidate genes. By taking genetic, bioinformatics, molecular and functional data into account, better insights into the molecular pathogenesis of HSCR should be gained. In this project, two sporadic long-segment HSCR cases were analysed by whole exome sequencing in a trio-based setup and by genotyping of non-coding risk single nucleotide polymorphisms. In both patients, bioinformatic analyses of exome-wide sequencing data led to the identification of rare structural (copy number variations (CNVs)) and single nucleotide variants (SNVs). To narrow down the list of HSCR candidate genes, rare SNVs were further filtered. Finally, four candidate genes (ATP7A, SREBF1, ABCD1 and PIAS2) which were so far not reported in the context of HSCR, were selected for detailed investigations. Extensive mRNA and protein expression analyses confirmed the expression of these candidates in relevant murine gastrointestinal tissues of different developmental stages and thereby validated their putative relevance for the HSCR aetiology. Moreover, additional HSCR patients carrying rare variants in SREBF1 and PIAS2 were identified. To further assess functionally the neuronal specific role of the candidates, the CRISPR/Cas9 technology was applied in a human neuroblastoma cell line. Gene-specific knockout (KO) cell clones were generated for three candidate genes and the major HSCR susceptibility locus RET, while genome editing was not successful for PIAS2. KO clones were investigated on morphological and functional level by a comparison to a mock control clone. Comparative analyses revealed variable differences for the individual gene-specific KO clones in the differentiation behaviour, proliferation and migration capacity as well as in cell survival during neuronal differentiation. To evaluate all findings of this complementary project, a HSCR risk scoring system was applied. According to the gained risk scores, all four selected HSCR candidates could be classified as relevant for the development of HSCR. Like this, the suitability of the presented research approach for identification and characterization of novel HSCR candidates was validated. It is envisioned to apply the established study pipeline to primary ENS-like model systems to confirm the findings of this project. Moreover, these analyses could help to dissect the candidate gene’s relevance for HSCR in detail and gain insights into affected molecular pathways. II Abstract Zusammenfassung III ZUSAMMENFASSUNG Die neurobiologische Entwicklungsstörung Morbus Hirschsprung (MH) repräsentiert die häufigste Ursache für angeborene Darmobstruktion und ist durch das Fehlen von enterischen Neuronen (Aganglionose) in spezifischen Abschnitten des Kolons charakterisiert. Diese Aganglionose resultiert aus Dysfunktionen in den Neuralleistenzellen (NLZ), welche für die Bildung des enterischen Nervensystems (ENS) im Rahmen der Embryogenese verantwortlich sind. Im Speziellen sind die NLZ- abgeleiteten Vorläuferzellen entweder in ihrer Proliferation, der Migration, der Differenzierung oder dem Zellüberleben gestört. Das Hauptsymptom von MH ist die Bildung eines Megakolons. Die standardmäßige Behandlung von MH-Patienten liegt in der operativen Entfernung des aganglionären Darmsegmentes, wobei funktionelle Darmbeschwerden in einem Teil der Patienten auch lebenslang persistieren. Auf genetischer Ebene wird MH als seltene und multifaktorielle Erkrankung klassifiziert. Bis heute sind mehr als 20 Gene, inklusive des bisher beschriebenen Hauptrisikolocus RET, als krankheitsauslösend beschrieben und viele weitere Gene wurden mit der Pathogenese in Verbindung gebracht. Dennoch ist die genetische Ursache in der Mehrheit der MH-Patienten bisher ungeklärt. Next- generation-sequencing Verfahren ermöglichen die schnelle Entschlüsselung der genetischen Architektur von Individuen. Die Auswahl der relevantesten genetischen Informationen und deren Korrelation mit den Pathomechanismen ist jedoch insbesondere im Zusammenhang mit komplexen Erkrankungen, wie MH, eine große Herausforderung. Zielsetzung dieses Projektes war die Etablierung einer komplementären Studienpipeline zur Identifizierung und Charakterisierung neuer MH- Kandidatengene. Die Betrachtung von genetischen, bioinformatischen, molekularen und funktionellen Daten soll zu einem besseren Verständnis der molekularen MH-Pathomechanismen beitragen. Im Rahmen dieser Studie wurden zwei sporadische, langstreckige MH-Patienten mittels Trio-basierter Exom-weiter Sequenzierung analysiert und für nicht-codierende Risiko-Polymorphismen genotypisiert. Die bioinformatische Analyse der Exom-weiten Sequenzdaten führte zur Identifizierung von seltenen strukturellen (Kopienzahlvariationen) und Einzelnukleotid-Varianten in beiden Patienten. Weitere Filterschritte wurden genutzt, um aus der Liste an seltenen Einzelnukleotid-Varianten die vielversprechendsten Genloci auszuwählen. Schlussendlich konnten somit vier Kandidatengene (ATP7A, SREBF1, ABCD1 und PIAS2), die bisher nicht mit MH beschrieben worden waren, für weitere Analysen bestimmt werden. Detaillierte Expressionsanalysen auf mRNA und Proteinebene zeigten, dass alle Kandidaten in murinem gastrointestinalem Gewebe zu relevanten Entwicklungsstadien exprimiert werden. Somit bestätigte sich eine putative Relevanz dieser Gene für die MH-Pathogenese. Zusätzlich konnten weitere MH-Patienten als Träger von seltenen Varianten in SREBF1 oder PIAS2 identifiziert werden. Um die neuronale Rolle der Kandidatengene experimentell zu untersuchen, wurde die CRISPR/Cas9 Methode in einer humanen Neuroblastomzelllinie angewandt. Gen-spezifische Knockout (KO) Zellklone konnten für drei Kandidaten und den bisher beschriebenen MH- Hauptrisikolocus RET generiert werden, wobei die Genomeditierung für PIAS2 nicht erfolgreich war. Die Gen-spezifischen KO Klone wurden für morphologische und funktionelle Analysen verwendet und hierbei mit einem Mock Kontrollklon verglichen. Diese vergleichenden Analysen zeigten variable Unterschiede in den individuellen KO Klonen im Differenzierungs-, Proliferations-, Migrations- und Zellapoptose-Verhalten. Um alle Ergebnisse dieser Studie abschließend bewerten zu können, wurde ein Risiko-Klassifizierungssystem genutzt. Die entsprechenden Risikowerte belegten eine MH- IV Zusammenfassung Relevanz für alle vier Kandidaten. Auf diese Weise konnte die Eignung der komplementären Studienpipeline zur Identifizierung und Charakterisierung neuer MH-Kandidatengene validiert werden. Um die Daten dieser Arbeit zu bestätigen, ist anvisiert, die etablierte Studienpipeline zukünftig auch in einem primären ENS-ähnlichen Zellkulturmodellsystem anzuwenden. Die entsprechenden Analysen könnten dazu beitragen, die Relevanz der Kandidatengene detailliert zu analysieren und somit Einblick in die betroffenen molekularen Signalwege zu erhalten. Presentations and Publications V PRESENTATIONS AND PUBLICATIONS Data generated within this project were already/will be presented at the following conferences: • Retreat of the ”Interdisciplinary center for neurosciences” (IZN) Heidelberg; July, 2016, 2018 and 2019, Schöntal (Germany); Poster • 24th annual meeting of the German Society of Neurogastroenterology and Motility; March 10-12, 2017, Berlin (Germany); Talk • NeuroGASTRO 2019 Biennal Meeting of the European Society of Neurogastroenterology and Motility; September 5-7, 2019, Lisbon (Portugal); Poster The following publications resulted/will result from this project and additional work: • Schmitteckert, S., Mederer, T., Niesler, B.; 2016;
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