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The Genetic Heterogeneity of Brachydactyly Type A1: Identifying the Molecular Pathways

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The genetic heterogeneity of brachydactyly type A1: Identifying the molecular pathways Lemuel Jean Racacho Thesis submitted to the Faculty of Graduate Studies and Postdoctoral Studies in partial fulfillment of the requirements for the Doctorate in Philosophy degree in Biochemistry Specialization in Human and Molecular Genetics Department of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa © Lemuel Jean Racacho, Ottawa, Canada, 2015 Abstract Brachydactyly type A1 (BDA1) is a rare autosomal dominant trait characterized by the shortening of the middle phalanges of digits 2-5 and of the proximal phalange of digit 1 in both hands and feet. Many of the brachymesophalangies including BDA1 have been associated with genetic perturbations along the BMP-SMAD signaling pathway. The goal of this thesis is to identify the molecular pathways that are associated with the BDA1 phenotype through the genetic assessment of BDA1-affected families. We identified four missense mutations that are clustered with other reported BDA1 mutations in the central region of the N-terminal signaling peptide of IHH. We also identified a missense mutation in GDF5 cosegregating with a semi-dominant form of BDA1. In two families we reported two novel BDA1-associated sequence variants in BMPR1B, the gene which codes for the receptor of GDF5. In 2002, we reported a BDA1 trait linked to chromosome 5p13.3 in a Canadian kindred (BDA1B; MIM %607004) but we did not discover a BDA1-causal variant in any of the protein coding genes within the 2.8 Mb critical region. To provide a higher sensitivity of detection, we performed a targeted enrichment of the BDA1B locus followed by high-throughput sequencing. We report the identification of a novel 9.5 Kb intergenic tandem duplication in two unrelated BDA1- affected families. In-vitro and in-vivo reporter assays demonstrated the enhancer activity of noncoding conserved sequence elements found within the duplicated interval. We also show an upregulation of the neighboring genes, NPR3 and PDZD2, in the patients' fibroblasts that suggests a gain-of-function through the duplication of cis-regulatory elements on dose sensitive genes. By expanding the repertoire of BDA1-causing ii mutations in IHH, GDF5, BMPR1B and at the BDA1B locus, we have begun to elucidate a common genetic pathway underlying phalangeal formation and elongation. iii Acknowledgements I am blessed to have had good people guide and direct me through a remarkable journey of learning, sacrifice and perseverance. I am grateful to Dr. Dennis Bulman for taking me under his wings as a graduate student. As a friend, mentor and supervisor he has always found a way to support me with patience and understanding. Furthermore, he has helped shape my research aptitude by teaching me the value of simplicity and clarity. From very humble beginnings in London, Ontario to the new setup in Ottawa, my passion for human genetics has followed in his footsteps. I would also like to thank my esteemed thesis advisory committee, Drs. Jeff Dilworth, Rashmi Kothary and David Picketts, for insightful conversations and very sound advice. I am extremely thankful for Dr. David Picketts and his laboratory for adopting me during the “endless” move. The BDA1 project would have not produced fruitful results if it were not for the comradery and the work of the Bulman lab personnel, past and present, notably Tara Read. To sum up the work atmosphere, one former Bulmanite so boldly and ridiculously stated “It was the bestest of times and the worstest of times, but mostly the bestest”. I would like to thank long-time colleague Ruobing Zou for helping me with many aspects of lab life. Thank you Michael Huh and Matt Todd for countless and endless conversations on “abstract science” with a healthy dose of craftbeer. Most importantly, I would like to thank my family who always remind me that “in your ways always acknowledge Him”. Thank you Mom and Dad for your endless support and love. To my wife Aliesha who has given me tremendous love and support during the ups and downs, I am eternally thankful to have you stand by my side. And to my son Noah for giving me a great reason to finish. iv Table of Contents Abstract .............................................................................................................................. ii Ackowledgements ............................................................................................................. iv Table of Contents ...............................................................................................................v List of Abbreviations ....................................................................................................... ix List of Figures ................................................................................................................ xvii List of Tables .................................................................................................................. xix Chapter 1. Introduction ....................................................................................................1 1.1 The brachydactylyies ..................................................................................................1 1.2 Brachydactyly type A1 ...............................................................................................4 1.2.1 Clinical description ..............................................................................................4 1.2.2 Epidemiology ......................................................................................................7 1.2.3 Historical perspective ..........................................................................................8 1.2.4 Genetic heterogeneity ..........................................................................................9 1.2.4.1 Mutation spectrum of IHH and GDF5 .......................................................10 1.2.4.2 BDA1B locus at chromosome 5p13.3 ........................................................16 1.2.5 Genetic models of BDA1 ..................................................................................18 1.3 The hedgehog signaling pathway .............................................................................21 1.4 Embryonic limb development ..................................................................................24 1.4.1 Proximal-distal growth ......................................................................................27 1.4.2 Anterior-posterior growth ..................................................................................28 1.5 Endochondral ossification ........................................................................................30 1.6 Growth plate dynamics .............................................................................................33 1.7 Human digit formation .............................................................................................36 1.8 Digit development and the current working model of BDA1 ..................................37 1.9 The current state-of-the-art detection of Mendelian traits........................................39 Chapter 2. Project goals ..................................................................................................40 2.1 Rationale ...................................................................................................................40 2.2 Hypotheses ...............................................................................................................41 2.3 Specific aims ............................................................................................................41 Chapter 3. Examining the mutation spectrum of IHH in causing BDA1 ...................42 3.1 Preface ......................................................................................................................42 3.2 Manuscript No. 1: Brachydactyly A-1 mutations restricted to the central region of the N-terminal active fragment of Indian Hedgehog .....................................................43 v 3.3 Manuscript Abstract .................................................................................................44 3.4 Introduction ..............................................................................................................45 3.5 Materials and Methods .............................................................................................46 3.6 Results ......................................................................................................................48 3.7 Discussion ................................................................................................................52 3.8 Acknowledgements ..................................................................................................56 3.9 Cited References ......................................................................................................57 3.10 Manuscript Figures, Tables and Legends ...............................................................61 3.11 Manuscript Supplementary Information ................................................................65 Chapter 4. Examining the genetic contribution of GDF5 in BDA1 ............................66 4.1 Preface ......................................................................................................................66 4.2 Manuscript No. 2: Mutations in GDF5 presenting as semi-dominant brachydactyly A1 ...................................................................................................................................67
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