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The Genetic and Molecular Characterization of the Polycystic Kidney Disease-Causing Mouse Gene Bicc1

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The Genetic and Molecular Characterization of the Polycystic Kidney Disease-Causing Mouse Gene Bicc1 THE GENETIC AND MOLECULAR CHARACTERIZATION OF THE POLYCYSTIC KIDNEY DISEASE-CAUSING MOUSE GENE BICC1 by Sarah J. Price Dissertation submitted to the Graduate College of Marshall University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences Approved by Dr. Elizabeth C. Bryda, Committee Chairperson Dr. Beverly C. Delidow Dr. Susan H. Jackman Dr. Donald A. Primerano Dr. Monica A. Valentovic Department of Microbiology, Immunology, and Molecular Genetics Joan C. Edward School of Medicine Marshall University Huntington, WV April 2004 Copyright© 2004 Keywords Listing: genetics, polycystic kidney disease, cilia, chromosome mapping, RNA-binding ABSTRACT THE GENETIC AND MOLECULAR CHARACTERIZATION OF THE POLYCYSTIC KIDNEY DISEASE-CAUSING MOUSE GENE BICC1 by Sarah J. Price Polycystic kidney disease (PKD) is one of the most common hereditary diseases and is characterized by progressive cyst formation, substantial renal enlargement, and frequently, progression to end-stage renal disease. One way to learn more about the etiology of this disease is to study mouse models that imitate the human situation. The juvenile congenital polycystic kidney disease (jcpk) gene on mouse Chromosome 10 has been found to cause a severe, early onset form of PKD when inherited in an autosomal recessive manner (Flaherty et al., 1995). Previous genetic studies mapped the jcpk locus to a 1 cM region on mouse Chromosome 10 between the markers D10Mit115 and D10Mit173 (Bryda et al., 1996). To positionally clone this gene, high resolution genetic and radiation hybrid maps were generated along with a detailed physical map of the critical region thought to contain the jcpk gene. Fine mapping studies allowed extensive reduction of this region to a section of mouse Chromosome 10 contained within three Bacterial Artificial Chromosomes (BACs). Nucleotide sequence analysis was performed to determine the presence of transcribed genes within this section of the chromosome. The only predicted gene was the mouse homologue of the Drosophila gene Bicaudal-C (Bicc1). Bicc1 was evaluated as a disease-susceptibility gene by examining the sequence of the Bicc1jcpk allele for mutations using a combination of RT-PCR and sequence analysis. A single base-pair change (G to A) was detected in the consensus splice acceptor site of exon 3. This frameshift mutation produces a premature stop codon predicted to result in a truncated protein. The function of the Bicc1 protein is unknown; however, several functional domains have been identified: three K Homology (KH) RNA binding domains and one sterile alpha motif (SAM). Ribonucleotide homopolymer analysis determined that Bicc1 binds RNA in vitro. In preliminary analyses of PKD-affected Bicc1jcpk/jcpk mice, left/right patterning defects including dextrocardia and lung isomerism were identified in one animal. The present work has enabled the identification of a gene, Bicc1, previously unknown to be involved in PKD pathogenesis and begins to explore the role of this gene and its corresponding protein in the kidney. DEDICATION I would like to dedicate this dissertation to my parents. Without their understanding, patience and love, the completion of this work would not have been possible. iii ACKNOWLEDGMENTS I would like to thank the members of my committee for their guidance and support. Their firm direction has been most appreciated. I would also like to thank the members of the Department of Microbiology, Immunology, and Molecular Genetics for their encouragement and assistance. I would like to personally thank Bryan Brubaker, Bryan O’Dell, William Ian Towler, and Jad Walters for their dedication and good humor. I would also like to acknowledge my friends and family for their undying patience. Finally, I would like to thank my mentor and friend, Dr. Elizabeth C. Bryda. From the beginning she had confidence in my abilities to not only complete a degree, but to complete it with excellence. iv TABLE OF CONTENTS ABSTRACT ......................................................................................................................ii DEDICATION...................................................................................................................iii ACKNOWLEDGMENTS ..................................................................................................iv TABLE OF CONTENTS ...................................................................................................v LIST OF TABLES ............................................................................................................vi LIST OF FIGURES .........................................................................................................vii CHAPTER I.......................................................................................................................1 INTRODUCTION................................................................................................................1 Purpose of the Research.........................................................................................................1 Significance of the Research...................................................................................................2 Organization of the Dissertation..............................................................................................2 CHAPTER II......................................................................................................................4 REVIEW OF THE LITERATURE...........................................................................................4 Polycystic Kidney Disease ......................................................................................................4 Murine Models for Human Disease.......................................................................................14 Ciliocentric Theory of PKD Pathogenesis .............................................................................22 Vertebrate Left-Right Asymmetry..........................................................................................27 Summary ...............................................................................................................................29 CHAPTER III...................................................................................................................30 MATERIALS AND METHODS............................................................................................30 Genetic and Physical Mapping..............................................................................................30 Gene Identification ................................................................................................................43 RNA Analysis.........................................................................................................................48 Protein Analysis.....................................................................................................................54 RNA Binding Study................................................................................................................59 Asymmetry Study ..................................................................................................................62 CHAPTER IV ..................................................................................................................63 RESULTS ......................................................................................................................63 Genetic and Physical Mapping..............................................................................................63 Gene Identification ................................................................................................................72 RNA Analysis.........................................................................................................................84 Protein Analysis...................................................................................................................118 RNA Binding Study..............................................................................................................126 Asymmetry Study ................................................................................................................129 CHAPTER V .................................................................................................................132 DISCUSSION................................................................................................................132 Summary and Conclusions .................................................................................................132 Future Directions .................................................................................................................149 APPENDIX A ................................................................................................................152 APPENDIX B ................................................................................................................155 APPENDIX C ................................................................................................................160 APPENDIX D ................................................................................................................162 APPENDIX E ................................................................................................................165 APPENDIX F.................................................................................................................173
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