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Genetic and Functional Studies of Hirschsprung Disease

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Genetic and Functional Studies of Hirschsprung Disease Genetic and Functional Studies of Hirschsprung Disease Rajendra Kumar Chauhan The work described in this thesis was financially supported by grants from ZonMW (TOP-subsidie 40-00812-98-10042) and the Maag lever Darm stichting (W009-62). All research described in the PhD thesis was conducted at the Department of Clinical genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. Part of this work was conducted on behalf of the International Hirschsprung Disease Consortium. The production costs of the thesis were supported by: Erasmus University Rotterdam, The Netherlands Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands ISBN: 978-90-8219-688-7 Cover: Rajendra Kumar Chauhan, Chaitali Paul and Tom de Vries-Lentsch Chapter illustrations: Chaitali Paul Layout: Chaitali Paul Printing: PrintSupport4U Copyright © R. K. Chauhan, 2016, Rotterdam, The Netherlands All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means, without prior permission of the author. Genetic and Functional Studies of Hirschsprung Disease Genetische en Functionele Studies voor ziekte van Hirschsprung Thesis to obtain the degree of Doctor from the Erasmus University Rotterdam by command of the rector magnificus Prof.dr. H.A.P. Pols and in accordance with the decision by the Doctorate Board. The public defense shall be held on Tuesday 1 November 2016 at 13:30 hrs by Rajendra Kumar Chauhan born in Sarkaghat, Mandi, India Erasmus University Rotterdam Doctoral Committee: Promoter: Prof.dr. R.M.W. Hofstra Assessment committee: Prof.dr. D. Tibboel Prof.dr. R. Willemsen Dr. I. Shepherd Co-promoters: Dr. B.J.L. Eggen Dr. A.J. Burns Table of Contents List of Abbreviations 6 Chapter 1 General Introduction and Scope of the Thesis 9 Chapter 2 De novo mutation in Hirschsprung patients link Central 37 Nervous System genes to the development of the Enteric Nervous System Chapter 3 Oligogenic inheritance in Hirschsprung disease: 85 implications of RET & Hedgehog Signaling in ENS development Chapter 4 Identification of predictive regulatory sequences for 115 gut development Chapter 5 Overexpression of the chromosome 21 gene ATP50 127 results in fewer enteric neurons: the missing link between Down syndrome and Hirschsprung disease? Chapter 6 Functional analysis of Hirschsprung disease genetic 153 data using the zebrafish model Chapter 7 General Discussion and Future Perspectives 173 Appendix 185 Summary 186 Samenvatting 190 Curriculum Vitae 194 List of Publications 195 PhD Portfolio 197 Acknowledgements 199 List of Abbreviations ATP5O ATP Synthase, H+ Transporting, Mitochondrial F1 Complex, O Subunit 5HT 5-hydroxytryptamin ARNT2 Aryl-hydracarbon receptor translocator 2 ARTN Artemin ASD Autism spectrum disorder AVPR2 Arginine Vasopressin Receptor2 BWA Burrows-Wheeler aligner CCHS Congenital Central Hypoventilation syndrome CGRP Calcitonin gene-related peptide Chr Chromosome CNS Central nervous system CNVs Copy number variants DAPPLE Disease Association Protein-Protein Link Evaluator DHH Desert hedgehog DNA Deoxyribonucleic acid DNM De novo mutation DNMT3B DNA (Cytosine-5-)-Methyltransferase 3 Beta DPF Days post fertilization DS Down syndrome DSCAM Down syndrome cell adhesion molecule ECE1 Endothelin converting enzyme 1 EDC Erasmus Dierexperimenteel Centrum EDN3 Endothelin 3 EDNRB Endothelin receptor type B EGF Epidermal growth factor EMT Epithelial to mesenchymal transformation ENCC Enteric neural crest cells ENS Enteric nervous system ERK Extracellular signal–regulated kinase FD Familial dysautonomia GATK Genome Analysis Toolkit GDNF Glial cell line-derived neurotrophic factor GDNF family receptor alpha-1 GI Gastrointestinal GLIGFRα1 GLI Family Zinc Finger GOSHS Goldberg-Shprintzen syndrome GPI Glycosylphosphatidylinositol GWAS Genome wide association studies hESCs Human embryonic stem cells 6 Hh Hedgehog HNK1 Human natural killer-1 HOXB5 Homeobox B5 Hsa21 Human chromosome 21 HSCR Hirschsprung disease ICC Interstitial cell of cajal IGV Integreted Genome Viewer IHH Indian hedgehog IKBKAP Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex associated protein IPA Ingenuity pathway analysis iPS Induced pluripotent stem (iPS) JAK/STAT Janus kinase/signal transducers and activators of transcription JNK Jun amino-terminal kinase KBP Kinesin binding protein KIF26A Kinesin Family Member 26 A L1CAM L1 Cell Adhesion Molecule L-HSCR Long segment Hirschsprung disease LOD Logarithm of the odds LOF Loss of function LRBA LPS Responsive Beige-Like Anchor Protein MEN2A Multiple endocrine neoplasia of type 2A MEN2B Multiple endocrine neoplasia of type 2B MO Morpholino mRNA Messenger ribonucleic acid MTC Medullary thyroid carcinoma NAV2 Neuron Navigator 2 NCC Neural crest cells NCLN Nicalin NCSC Neural crest stem cell NGS Next Generation Sequencing NKA Neurkinin A NLBs Neurosphere like bodies NO Nitric oxide NPC Neural progenitor cell NRG1 Neuregulin 1 NRTN Neuturin NUP98 Nucleoporin 98kDa NXF Neuronal PAS domain protein 4 (NPAS4) OSCP Oligomycin Sensitivity Conferral Protein PACAP Pituitary adenylate cyclase activating peptide 7 PCR Polymerase chain reaction PHOX2B Paired-like homeobox 2b PI3K/AKT Phosphatidylinositol 3-kinase/AKT PKC Protein kinase C PNS Peripheral nervous system PSPN Persephin PTCH1 Patched 1 QA Quality assesment RAIR Recto-anal inhibitory reflex RAS/MAPK Ras/mitogen activated protein kinase RET Rearranged during transfection SBMOs Splice-blocking morpholinos SDM Site directed mutagenesis SEMA Semaphorin SHH Sonic hedgehog S-HSCR Short segment Hirschsprung disease SMO Smoothened SNP Single nucleotide polymorphism SNVs Single nucleotide variants SOX10 SRY (Sex determining region Y)-box 10 TBATA Thymus, Brain And Testes Associated TBMOs Translation-blocking morpholinos TCA Total colonic aganglionosis TF Transcription factor TIA Total intestinal aganglionosis TSS Transcriptional Start Site TTF1 Thyroid transcription factor 1 UTR Untranslated region VCF Variant call format VIP Vasoactive intestinal polypeptide WES Whole Exome Sequencing WGS Whole genome sequencing WISH Whole mount in situ hybridization WS4 Waardenburg syndrome, type IV WT Wild type ZEB2 Zinc finger E-box-binding homeobox2 ZIRC Zebrafish International Resource Centrum 8 CHAPTER 1 General Introduction and Scope of the Thesis Chapter1 ABSTRACT Complex (genetic) diseases are caused by many genetic, epigenetic and environmental factors that in concert result in a disease phenotype. Identifying the contribution of an individual gene(s), epigenetic aberrations or environmental factors is extremely challenging. It is this understanding of complex diseases that has become the major topic in the field of human genetics. Hirschsprung disease (HSCR) is one such complex genetic disorder. It is the most common forms of congenital obstruction of the bowel, and results from a failure of the neural crest-derived progenitor cells of the enteric nervous system (ENS) to migrate, proliferate, differentiate or survive in the gut wall during early embryonic development. The phenotype of this defect(s) is a variable length of aganglionosis in the distal part of the bowel. Since the 1990s, a multitude of genetic studies based on linkage analysis, homozygosity mapping, and genome wide association studies (GWAS) resulted in the identification of many susceptibility loci and genes involved in this complex disease. In the last decade, extraordinary progress has been made in genome sequencing technologies, collectively referred to as Next Generation Sequencing (NGS). This has greatly enhanced our knowledge and understanding of the role of novel genes and genetic variability in the pathogenesis of diseases. Combining NGS-based strategies with traditional linkage or expression studies has resulted in the identification of new HSCR genes. Moreover, the use of in vitro and in vivo assays to establish genotype-phenotype associations has further enhanced our understanding of the different mechanisms associated with ENS development in general and HSCR in particular. In this thesis, we aim to better understand and unravel the complexity of HSCR genetics using genomics approach and in vivo modelling of HSCR in zebrafish model. THE ENTERIC NERVOUS SYSTEM (ENS) The gastrointestinal (GI) tract is an internal organ which requires the coordinated activity of its neuromuscular components for the mixing and propulsion of food, for breakdown of complex foods during digestion, and for secretion, absorption and excretion. The functions of the GI tract are governed by the ENS, an extensive network of neurons and glial cells that form a meshwork of interconnected ganglia along the entire bowel1. These comprise the outer myenteric (Auerbach’s) plexus which resides between the circular and longitudinal smooth muscle layers, and the inner submucosal (Meissner’s) plexus. 10 General Introduction and Scope of the Thesis The myenteric plexus provides motor innervation to the muscle layers and secretomotor innervation to the mucosa1. Embryonic origin of ENS 1 The entire ENS is derived from the neural crest (NC). The NC is a transient population of cells that emerges/detaches from the dorsal neural tube during early embryonic development. This happens after undergoing epithelial to mesenchymal transformation (EMT) and these neural crest cells (NCC) start migration to various locations throughout the embryo. NCC are multipotent and differentiate into a wide range of cell types during vertebrate development including elements of the craniofacial
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