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Proquest Dissertations mn u Ottawa l.'Univcrsilc can.ifficn/ic Canada's university FACULTE DES ETUDES SUPERIEURES 11=1 FACULTY OF GRADUATE AND ET POSTOCTORALES U Ottawa POSDOCTORAL STUDIES L'Urriversittf canadienne (Canada's university Fabin Han AUTEUR DE LA THESE / AUTHOR OF THESIS Ph.D. (Microbiology and Immunology) GRADE/DEGREE Department of Biochemistry, Microbiology and Immunology Characterization of the Genes for Myoclonus-Dystonia TITRE DE LA THESE / TITLE OF THESIS Dennis Bulman EXAMINATEURS (EXAMINATRICES) DE LA THESE /THESIS EXAMINERS John Bell Peter Ray Robert Korneluk Catherine Tsilfidis Gary W. Slater. Le Doyen de la Faculte des etudes superieures et postdoctorales / Dean of the Faculty of Graduate and Postdoctoral Studies Characterization of the Genes for Myoclonus-Dystonia By Fabin Han Thesis Submitted to the School of Graduate Studies in Partial Fulfillment of the Requirements for the Degree of Doctorate of Philosophy Department of Biochemistry, Microbiology and Immunology, Graduate Collaborative Program in Human and Molecular Genetics, Faculty of Medicine University of Ottawa Copyright by Fabin Han, 2007 Ottawa, Canada Library and Bibliotheque et 1*1 Archives Canada Archives Canada Published Heritage Direction du Branch Patrimoine de I'edition 395 Wellington Street 395, rue Wellington Ottawa ON K1A0N4 Ottawa ON K1A0N4 Canada Canada Your file Votre reference ISBN: 978-0-494-49354-0 Our file Notre reference ISBN: 978-0-494-49354-0 NOTICE: AVIS: The author has granted a non­ L'auteur a accorde une licence non exclusive exclusive license allowing Library permettant a la Bibliotheque et Archives and Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par telecommunication ou par Plntemet, prefer, telecommunication or on the Internet, distribuer et vendre des theses partout dans loan, distribute and sell theses le monde, a des fins commerciales ou autres, worldwide, for commercial or non­ sur support microforme, papier, electronique commercial purposes, in microform, et/ou autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriete du droit d'auteur ownership and moral rights in et des droits moraux qui protege cette these. this thesis. Neither the thesis Ni la these ni des extraits substantiels de nor substantial extracts from it celle-ci ne doivent etre imprimes ou autrement may be printed or otherwise reproduits sans son autorisation. reproduced without the author's permission. In compliance with the Canadian Conformement a la loi canadienne Privacy Act some supporting sur la protection de la vie privee, forms may have been removed quelques formulaires secondaires from this thesis. ont ete enleves de cette these. While these forms may be included Bien que ces formulaires in the document page count, aient inclus dans la pagination, their removal does not represent il n'y aura aucun contenu manquant. any loss of content from the thesis. Canada Abstract: Myoclonus-dystonia (M-D; OMIM 159900) is an autosomal dominant movement disorder characterized by alcohol responsive myoclonic jerks typically affecting the arms and axial muscles. Mutations in the epsilon-sarcoglycan (SGCE) gene on chromosome 7q21 were shown to cause M-D but not in all cases. Currently, in the literature mutations in SGCE are responsible for 20-50% of all cases of M-D. By direct sequencing, we have identified mutations in four families and we were able to find large deletions in two additional families using a semi-quantitative PCR-based DHPLC method. One of these families (family 2) has an 18 kb deletion that includes exons 2 and 3 while another family (family 6) has a 13 kb deletion covering exons 2 through 5. We have confirmed these large deletions by identifying the exact deletion breakpoints. In our cohort of 17 unrelated M-D families, 35% of patients with M-D have mutations in the SGCE gene. Previously, we characterized a large five-generation Canadian family with M-D (family 1) that did not have a mutation in SGCE and mapped a novel locus for this disorder to a 4 Mb region between the markers D18S1132 and D18S843 on 18pl 1 (OMIM number: 607488). Since additional informative STS markers were not found between the flanking recombinant and non- recombinant markers, we utilized single nucleotide polymorphisms (SNP) for fine-mapping. As a result, we identified three recombinant SNPs (rs385769, rs727951 and rs727952) in the proximal flanking region between markers D18S1163 and D18S843 in family 1. Our previous 4 Mb critical region has been reduced to 3.18 Mb, flanked by markers D18S1132 and rs385769. There are seven known genes and eight predicted genes within or very close to this region. We have sequenced all the exons and exon-intron boundaries of these seven known genes (MGC17515, ZFP161, EPB41L3 (KIAA0987), L3MBT4, ARHGAP28 (FLJ10312), LAMA1, and PTPRM) and four predicted genes (LOC388459, LOC388460, ii LOC400643 and LOC388461) without identifying the causative mutations. Future studies should be directed to the investigation of the functional effects of the known SGCE mutations using in vitro and in vivo models. With respect to the identification of a novel gene in family 1, we will focus on the novel transcripts in the critical region based on gene prediction and EST (expressed sequence tag) mapping. Once the second M-D causing gene is identified, we will perform gene expression and cellular localization analyses of the mutated and wild type protein in tissues and generate a mouse model. iii Acknowledgements After four years of hard work and diligent study, I have finished my graduate study with the submission of my PhD thesis. I would like first to thank my supervisors, Dr. Dennis E. Bulman and Dr. David A. Grimes for their careful mentorship, their unlimited patience and their enthusiastic encouragement in each step of my research project. I really appreciate that for all the experiments I did in this lab, they gave me the right direction, they carefully reviewed my research results, and they patiently listened to my explanations and discussed with me the critical issues on my work. Most importantly, they carefully corrected my abstracts, PowerPoint slide and poster presentations, and my paper drafts by showing me the basic word skills, presentation skills, and the skills to answer the questions asked by the audience to intensify my research abilities. In addition, they have provided me a lot of knowledge in molecular genetics, molecular biology, and bioinformatics as well as experimental skills in genotyping, genetic linkage analysis, PCR, RT-PCR, DNA sequencing, gene dosage analysis and so on. I will always remember their strict scientific attitudes and kindness in my future research no matter where I will go. Secondly, I would like to thank my thesis committee members, Dr. Rashmi Kothary and Dr. Ken Dimock for their professional advices, critical comments and constructive suggestions for the success of my research project. Thirdly, I would like to thank all the lab mates in Dr. Bulman's lab and my colleagues in other labs of the OHRI as well as in the Microbiology and Immunology Program at the University of Ottawa. Fourthly, I would like to thank all the clinicians who identified the families with myoclonus-dystonia and shipped blood samples of patients to our lab. Without their contributions, this thesis would never have been possible. These collaborators are: Dr. Antony E. Lang, Dr. Oksana Suchowersky, Dr. Daune McGregor, Dr. iv Galit Kleiner-Fisman, Dr. Peter Humphreys and Dr. Alan Fryer. Fifthly, I should thank all the M-D family members for their participation in this research project. I would also thank Canadian Institutes of Health Research (CIHR), Ontario Research Development Fund and The Dystonia Medical Research Foundation for their funding to support my research. Finally, I am greatly indebted to my beloved parents, my wife, my son and my other family members for their emotional support, concern and continuous encouragement during my PhD study. v Table of Contents Page Abstract ii Acknowledgements iv Table of Contents vi List of Figures xiii List of Tables xvi List of Abbreviations xvii Chapter 1: Introduction: Primary Dystonia and Myoclonus-Dystonia 1 1.1. The clinical manifestation and classification of dystonia 2 1.2. Genetics of dystonia 4 1.2.1. Autosomal dominant, early-onset dystonia (DYT1 or TOR1A) 7 1.2.2. X-linked dystonia-parkinsonism syndrome (DYT3) 8 1.2.3. Dopa-responsive dystonia (DYT5) 8 1.2.4. Autosomal dominant focal dystonia (DYT7) 10 1.2.5. Paroxysmal non-kinesigenic dyskinesia (PNKD or DYT8) 10 1.2.6. Inherited myoclonus-dystonia or myoclonus-dystonia (DYT11) 11 1.2.7. Rapid-onset dystonia-parkinsonism (RPD, DYT12) 11 1.3. Phenotypic characteristics of myoclonus-dystonia (M-D) 12 1.4. Myoclonus-dystonia and mutations in the SGCE gene 14 1.4.1. Linkage analysis localized the DYT11 locus to chromosome 7q21 14 1.4.2. Identified mutations in the s-sarcoglycan (SGCE) gene for M-D (DYT11) 15 vi 1.4.3. Genomic structure of the SGCE gene on chromosome 7q21 20 1.4.4. Expression patterns oftheSGCZimRNA and protein 22 1.4.5. Mutated SGCE in M-D families is maternally imprinted 23 1.4.6. Functional studies of the SGCE gene and knockout mouse models 25 1.5. Genetic heterogeneity of myoclonus-dystonia 29 1.6. Rationale, Hypothesis, and Aims 32 1.6.1. Rationale 32 1.6.2. Hypothesis 32 1.6.2. Aims 32 Chapter 2. Subjects and General Methodology 34 2.1. Phenotypic characteristics of the patients in our cohort of families with M-D 35 2.2. Isolation of genomic DNA from whole blood 41 2.3. Genotyping and linkage analysis methods 41 2.3.1. Genotyping 41 2.3.2. Linkage analysis ; 42 2.4.
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