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Genetic and Molecular Studies in Hyperinsulinemic Hypoglycemia and Congenital Polycystic Kidney Disease (HIPKD)

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Genetic and Molecular Studies in Hyperinsulinemic Hypoglycemia and Congenital Polycystic Kidney Disease (HIPKD) Genetic and molecular studies in Hyperinsulinemic Hypoglycemia and congenital Polycystic Kidney Disease (HIPKD) Anne Lore Kesselheim UNIVERSITY COLLEGE LONDON A thesis submitted to the University College London for the degree of Doctor of Philosophy June 2018 1 Declaration I, Anne Kesselheim confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Acknowledgement I would like to thank my supervisors Detlef Böckenhauer and Robert Kleta for offering me the opportunity and their trust to work on this project. I very much appreciate their guidance and support through the work presented in this thesis over the last three years. I am grateful to the J F Moorhead Trust for funding this work. I also thank all collaborators who were involved in this project. Thank you also to Michael Ludwig who encouraged me to move to London and has introduced me to Detlef and Robert. I sincerely thank Ben Davies for giving me the chance to work in his lab at the Wellcome Trust Centre for Human Genetics at the University of Oxford where I could spend nine months to work on my CRISPR-Cas9 experiments under his supervision. His support was of great value for me and this project and I have learned a lot during this time. I also would like to express my special gratitude to the Davies’ group who made me feel welcome from day one on and treated me as if I was part of their team. I in particular would like to thank Phalguni Rath for answering my countless questions around the CRISPR experiments, discussing results and the long hours spent in front of the FACS machine; Daniel Biggs for sharing his expertise in cell culture and his support whenever I needed it; Polinka Hernandez-Pliego for helping me genotyping hundreds of HepG2 clones. My thanks also go to all my colleagues at the Centre for Nephrology for their constant support, advice, patience and listening. My special thanks to Vaksha Patel for her professional and personal support throughout this PhD and helping me to keep up my stamina; Horia Stanescu and Chris Cheshire for conducting the extensive bioinformatic analyses and sharing the data which have substantial impact on this project. Thank you to my friends in London and Germany, in particular Steffi and Felice, for always being there for me especially when I was going through tough times. I am grateful to Grégory for his enduring patience, understanding and unconditional support. I cannot thank my family enough for their constant encouragement and understanding when I have not always been present in happy and sad situations. I express my greatest thanks to my mother Ulrike and my sister Steffi for their love, endless support and unwavering belief in me. Thank you for always being there for me. Finally, I dedicate this thesis to my father who left far too early and my beloved grandmother Lotti. 3 Abstract Background Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence (HIPKD) in 17 children from 11 unrelated families suggested a shared cause. Methods We ascertained the clinical phenotype and performed genetic studies. The effect of the identified shared mutation was assessed in vitro. Results All patients exhibited HI and enlarged polycystic kidneys. Whole genome linkage analysis in 5 informative families identified a single significant (LOD 6.5) locus on chromosome 16p13.2. A promoter mutation (c.-167G>T) in PMM2 was found in all patients, either homozygous or in trans with PMM2 coding mutations. Yet, typical systemic features of congenital disorder of glycosylation type 1a were absent and the diagnostic test of transferrin isoelectric focusing was normal. The promoter mutation showed decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggests an important role for ZNF143 for the formation of a chromatin loop including PMM2 that could affect tissue- specific transcription. In order to investigate this further in a chromatin conformation study a HIPKD cell model homozygous for the promoter mutation was generated with CRISPR-Cas9. Conclusions We report a rare disease characterized by the combination of hyperinsulinemic hypoglycemia and polycystic kidney disease. Our findings extend the spectrum of genetic causes for both disorders, provide insights into gene regulation and implicate glycosylation in the disease etiology. The identified promoter mutation appears critical for tissue-specific regulation of PMM2 transcription, leading to an organ-specific phenotype and explaining PMM2 pleiotropy. 4 Impact Statement The work undertaken during this project expands the spectrum of genetic causes for HI and PKD, relevant for clinical research and diagnosis. This study also provides critical insights into gene regulation and underlines the importance of studying the impact of non-coding variants in human disease. Furthermore, it indicates that the higher organisation of the genome essentially contributes to correct gene regulation and that extensive research on this topic is of great value for both, basic and medical research. The initial findings during this PhD have highlighted the dysfunctional gene regulation of the PMM2 promoter variant. This substantially has contributed to postulate a hypothesis for the potential disease mechanism in HIPKD and eventually has helped to draw the attention onto gene regulation and 3D chromatin conformation. In this thesis, the generation of a HIPKD cell model with the CRISPR-Cas9 technology will take the project to its next level and will enable us to study the 3D conformation in health and disease on the example of HIPKD. Hence, this work will provide new important details of the spatial organisation of the human genome in general and will help to understand interactions within the genome and how these are affected when a mutation lies in a gene regulatory element. In fact, about 30 million people in Europe are affected by rare diseases (same number in the US). 80% of rare disease worldwide are of genetic cause and often are life-threatening devastating disorders which frequently affect children. The major issue with rare diseases is the lack of treatment for most of them. Research on rare diseases significantly improves the understanding of biology and molecular mechanisms within the human body in health and disease, which is crucial for the identification of drug targets with the major goal of developing new treatments. These may not only benefit patients with the rare disease that led to the identification of the drug, but also for more common diseases. Moreover, extensive research on rare diseases can improve diagnosis and thereby avoid unnecessary treatments and improve and personalise disease management. Studies as conducted during this PhD with the aim to decipher a rare disease mechanism significantly contributes to the general understanding of biological processes important for human health and in particular the involvement of the non-coding genome and chromatin folding in human disease. More than a million enhancer elements are present within the human genome. Hence, it is not surprising that non-coding mutations which alter architectural modules can cause human disease. However, we are just at the beginning to understand how SNPs and structural variants impact genome folding. The combination of Hi-C data and gene editing tools such as CRISPR-Cas9 may allow for innovative new therapeutic inventions. These could be based on cell-related therapy and the insertion or elimination of architectural 5 modules. Thus, studies which focus on the 3D genome itself and the impact of non-coding variants on genome folding are needed to significantly improve diagnostic and potentially therapeutic outcomes valid for research, medicine and industry. 6 Table of contents CHAPTER 1: GENERAL INTRODUCTION 21 1.1 THE NEPHRON 21 1.2 RARE DISEASES AND HOW THEY TEACH US 23 1.3 CYSTIC KIDNEY DISEASES 24 1.3.1 AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) 27 1.3.1.1 Phenotype 27 1.3.1.2 Genetic cause and the encoded proteins 27 Polycystin 1 (PC-1) 28 Polycystin 2 (PC-2) 28 Function of polycystins 29 Mechanosensation and cilia 29 Involvement in signalling pathways 30 Cystogenesis 32 1.3.2 AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE (ARPKD) 35 Phenotype 35 Genetic cause and encoded protein 35 Fibrocystin, its function and cystogenesis 35 1.3.3 GLOMERULOCYSTIC KIDNEY DISEASE 36 1.4 THE ISLETS OF LANGERHANS OF THE HUMAN PANCREAS 38 1.5 PEPTIDE HORMONES SECRETED BY THE ISLETS OF LANGERHANS 39 1.5.1 PANCREATIC GLUCOSE HOMEOSTASIS BY INSULIN AND GLUCAGON - PRINCIPLE 39 1.5.2 INSULIN AND INSULIN SIGNALLING 40 1.5.3 GLUCAGON, GLUCAGON SECRETION AND SIGNALLING 42 1.5.4 SOMATOSTATIN 43 1.5.5 GHRELIN 44 1.5.6 PANCREATIC POLYPEPTIDE 45 1.6 THE INSULIN SECRETION PATHWAY 45 1.6.1 GLUCOSE INDUCED INSULIN SECRETION PATHWAY 45 1.6.1.1 Biphasic character of insulin release 47 1.6.1.2 Exocytosis of insulin granules 48 1.6.2 GLP-1 INDUCED INSULIN SECRETION PATHWAY 50 7 1.7 HYPERINSULINEMIC HYPOGLYCAEMIA (HYPERINSULINISM) 52 1.7.1 GENETIC CAUSE, ENCODED PROTEINS AND MOLECULAR PATHOMECHANISM 52 1.7.1.1 KATP channel mutations (KCNJ11, ABCC8) 53 1.7.1.2 Glutamate dehydrogenase mutations (GLUD1) 53 1.7.1.3 Glucokinase mutations (GCK) 54 1.7.1.4 Solute carrier family 16, member 1 mutations (SLC16A1) 54 1.7.1.5 HNF4A and HADH mutations 54 1.8 CONGENITAL DISORDERS
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