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Genetic Investigation of Kidney Disease

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Genetic Investigation of Kidney Disease Genetic Investigation of Kidney Disease A thesis submitted for the Degree of Doctor of Philosophy 2010 Daniel P. Gale UCL Division of Medicine Declaration I, Daniel Philip Gale, 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 Acknowledgements I would like to thank the patients and families who participated in this study and from whom I have learned so much. Without their trust, hospitality and generosity none of this would have been possible. I am especially glad to have the opportunity to thank my supervisor, Professor Patrick Maxwell whose support, encouragement and wisdom have been so valuable in both the laboratory and the hospital. I would also like to thank the Medical Research Council for funding this work. I also owe a debt of gratitude to my colleagues in the laboratories and hospitals in which I worked – especially Drs Sarah Harten, Tapan Bhattacharyya, Alkis Pierides, Margaret Ashcroft and Deepa Shukla; and to my collaborators, in particular Professors Terry Cook, Ted Tuddenham and Peter Robbins, and Drs Matthew Pickering, Nick Talbot and Elena Goicoechea de Jorge. I would also like to thank Guy Neild, Tom Connor, Tony Segal and Oliver Staples for many stimulating discussions, and my family and friends for their unwavering support and interest. 3 Abstract Kidney disease is an important contributor to the burden of ill-health worldwide. Genetic factors have an important role in determining which people are affected by kidney disease, and this study aimed to identify the genes responsible for disease in families in which unusual kidney diseases were transmitted in a pattern suggesting autosomal dominant inheritance. I performed genome-wide single nucleotide polymorphism-based linkage studies and identified two new human disease genes. Hypoxia Inducible Factor-2α (HIF2α) is a widely expressed transcription factor which is rapidly broken down in the presence of oxygen. When oxygenation is reduced it activates the transcription of many genes, including erythropoietin which stimulates red blood cell production. I identified a heterozygous activating mutation of HIF2α which cosegregated with autosomal dominantly inherited erythrocytosis and pulmonary arterial hypertension in a British family, producing a phenotype similar to the effects of high altitude exposure. In vitro studies demonstrated that the mutant protein has increased transcriptional activity under normoxia. This suggests that HIF2α plays an important role in regulating the organism-wide responses to oxygen availability. Complement Factor H Related protein 5 (CFHR5) is a homologue of the complement regulating protein Complement Factor H and is of incompletely understood function. I uncovered an in-frame heterozygous duplication of exons 2 and 3 of the CFHR5 gene which cosegregated with autosomal dominantly inherited microscopic and synpharyngitic macroscopic haematuria, glomerulonephritis and renal failure in 2 families with ancestry in the Troodos Mountains of Cyprus. The mutation results in the production of a protein with impaired affinity for complement deposited in the kidney. This disease, which I named CFHR5 nephropathy, is endemic in Cyprus, accounting for a significant proportion of renal disease on 4 the island, and may be amenable to systemic treatments. These findings implicate CFHR5 as a new and important regulator of complement in the human kidney. 5 Table of Contents List of Abbreviations .............................................................................................................. 18 Publications arising from this work ....................................................................................... 20 Chapter 1: Introduction ......................................................................................................... 21 1.1 The rationale for Genehunting .................................................................................... 22 1.2 Historical perspective ................................................................................................... 23 1.3 The whole genome era ................................................................................................ 25 1.4 Genetic kidney disease................................................................................................. 27 1.5 This study ..................................................................................................................... 28 Chapter 2: HIF2α Erythrocytosis and Pulmonary Hypertension ........................................... 29 2.1 Introduction ................................................................................................................. 30 2.1.1 Oxygen sensing in eukaryotes .............................................................................. 30 2.1.2 Oxygen, haematocrit and erythropoietin ............................................................ 31 2.1.2.1 Renal erythropoietin production ................................................................. 33 2.1.2.2 Hepatic Erythropoietin production .............................................................. 34 2.1.3 Regulation of erythropoietin gene expression .................................................... 35 2.1.4 Oxygen sensing by HIF ......................................................................................... 36 2.1.5 Regulation of HIF by oxygen ................................................................................ 37 2.1.5.1 Regulation of HIF destruction by PHD enzymes........................................... 38 2.1.5.2 Factor Inhibiting HIF ..................................................................................... 41 2.1.6 Effects of HIF activation ....................................................................................... 41 2.1.7 Role of different HIF subunits in the EPO response ............................................. 44 6 2.1.8 Genetic defects in the oxygen sensing pathway in humans ................................ 46 2.1.8.1 Von Hippel-Lindau disease ........................................................................... 46 2.1.8.2 Chuvash Polycythaemia ............................................................................... 47 2.1.8.3 PHD2 erythrocytosis ..................................................................................... 48 2.1.8.4 A novel HIF pathway disease? ...................................................................... 49 2.2 Clinical histories ........................................................................................................... 50 2.3 Genetic Investigation ................................................................................................... 55 2.3.1 Genome-wide SNP linkage and haplotype analysis ............................................. 58 2.3.2 HIF2α sequencing ................................................................................................. 60 2.3.2.1 HIF2α G2097A may be pathogenic .............................................................. 62 2.3.2.2 HIF2α G2097A is a rare mutation which segregates with disease ............... 63 2.4 HIF2α Arg537 functional studies .................................................................................. 65 2.4.1 HIF2α Arg537 has increased transcriptional activity ........................................... 65 2.4.2 Increased transcriptional activity of HIF2α Arg537 is oxygen-dependent ........... 69 2.5 HIF2α Erythrocytosis and pulmonary physiology ........................................................ 70 2.6 Summary ...................................................................................................................... 72 2.7 Discussion ..................................................................................................................... 74 2.7.1 Genetic adaptation to altitude ............................................................................. 76 2.7.1.1 Chronic Mountain Sickness .......................................................................... 76 2.7.1.2 Reproduction at high altitude ...................................................................... 80 2.7.1.3 Positive selection in Tibetans ....................................................................... 82 2.8 Conclusion .................................................................................................................... 84 7 Chapter 3: Identification of CFHR5 nephropathy .................................................................. 85 3.1 Introduction: Renal disease and Complement ............................................................ 86 3.2 Complement................................................................................................................. 88 3.3 The terminal pathway .................................................................................................. 89 3.4 The classical pathway ................................................................................................... 91 3.5 The mannose-binding lectin pathway .......................................................................... 91 3.6 The alternative pathway .............................................................................................. 92 3.7 Other mechanisms of AP convertase activation .......................................................... 93 3.8 Breakdown products of C3b........................................................................................
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