Lubov T. Timchenko Triple Repeat Diseases of the Nervous System Triple Repeat Diseases of the Nervous System Triple Repeat Diseases of the Nervous System Edited by Lubov T. Timchenko Department of Medicine Baylor College of Medicine Houston, Texas, U.S.A. Kluwer Academic / Plenum Publishers New York, Boston, Dordrecht, London, Moscow Library of Congress Cataloging-in-Publication Data CIP applied for but not received at time of publication. Triplet Repeat Disorders of the Nervous System Edited by Lubov T. Timchenko ISBN 0-306-47417-4 AEMB volume number: 516 ©2002 Kluwer Academic / Plenum Publishers and Landes Bioscience Kluwer Academic / Plenum Publishers 233 Spring Street, New York, NY 10013 http://www.wkap.nl Landes Bioscience 810 S. Church Street, Georgetown, TX 78626 http://www.landesbioscience.com; http://www.eurekah.com Landes tracking number: 1-58706-055-8 10 987654321 A C.I.P. record for this book is available from the Library of Congress. All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher. While the authors, editors and publisher believe that drug selection and dosage and the speci- fications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accu- mulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein. Printed in the United States of America. PREFACE World of Unstable Mutations The book “Triplet Repeat Diseases of the Nervous System” overviews the lat- est data on several disorders associated with unstable mutations. This field of re- search is progressing extremely fast. The number of polymorphic mutations and diseases caused by these mutations is increasing almost every month. There is a strong interest to molecular bases of triplet repeat disorders. This is explained by growing necessity to develop molecular approaches for cure of these diseases. There- fore, the authors of this book describe unstable mutations with the emphasis on molecular pathology. Broad discussion is presented on how polymorphic expan- sions cause cell dysfunction. • The first chapter of the book focuses on the molecular pathological pro- cesses that originate “unstable” mutations. The authors review several avail- able models by which normal “stable” region of DNA become pathogenic and discuss possible mechanisms causing DNA instability. • The other chapters of the book describe inherited diseases associated with different types of unstable mutations. Based on the location of mutation in the disease gene, polymorphic expansions of the nervous system can be divided into two major groups. First group includes disorders with unstable expansions within the open reading frame of the gene such as Spinocer- ebellar Ataxias caused by polyglutamine expansions. The second group in- cludes diseases caused by expansions situated within the untranslated re- gions of the gene. •In Chapter 3, the authors summarize comprehensive information (clinical, genetic, and molecular) on all known polyglutamine diseases with the em- phasis on the common and distinctive features between different disorders in this group. • Recent studies suggested that some Spinocerebellar Ataxias might be caused not by polyglutamine track, but by unstable repeats in untranslated regions of DNA. The authors in Chapter 4 discuss Spinocerebella Ataxia 10 that is associated with polymorphic ATTCT repeat in the intron of unknown gene. • The chapter 2 describes Myotonic Dystrophy 1 that is caused by unstable CTG repeats within the 3’ UTR of the disease gene. Multiple hypotheses v were proposed to explain this disease. The authors analyze several mouse models for DM1 disease and discuss how CTG repeat is expanded in pa- tients and why such expansion causes pathology. • Chapter 5 describes another example of disorder with polymorphic muta- tion in non coding region of the gene—Friedreich Ataxia. In this disease, GAA triplet repeat is located in the first intron of frataxin. The author pro- vides comprehensive information on clinical and genetic aspects of this disease and analyzes a variety of possible molecular pathways responsible for occurrence of mutation and development of pathology. What should we expect in future in this field? Identification of novel unstable mutations will be accompanied by identification of molecular pathways by which these mutations cause a disease. Emerging information from different fields of sci- ence (protein and RNA biology, physiology, crystallography, gene therapy, etc) will help to develop strategy to prevent and cure disorders with unstable mutations. The authors of this book are thankful to editorial coordinators and publishers for their support and tireless help. Lubov T. Timchenko Department of Medicine Baylor College of Medicine Houston, Texas, U.S.A. vi PARTICIPANTS Tetsuo Ashizawa Tohru Matsuura Department of Neurology Department of Neurology Baylor College of Medicine and Baylor College of Medicine and Veterans Affairs Medical Center Veterans Affairs Medical Center Houston, Texas 77030 Houston, Texas 77030 USA USA Alexis Brice Darren G. Monckton INSERM U289 Institute of Biomedical and Life Institut Fédératif di Recherche des Sciences Neurosciences The University of Glasgow Département de Génétique Glasgow, G12 8QQ Cytogénétique et Embryologie UK Groupe Hospitalier Pitié-Salpêtriére 75651 Paris Cédex 13 Massimo Pandolfo France Centre Hospitalier de la Université de Montréal Thomas A. Cooper Hopital Notre-Dame Departments of Pathology and 1560 rue Sherbrooke Est Molecular and Cell Biology Montréal, Quebec Baylor College of Medicine H2L 4M1 Canada Houston, TX 77030 USA Pawel Parniewski Centre for Microbiology and Virology Alexandra Dürr Polish Academy of Sciences INSERM U289 ul. Ludowa 106 Institut Fédératif di Recherche des 93-232 Lódz Neurosciences Poland Département de Génétique Cytogénétique et Embryologie Pawel Staczek Groupe Hospitalier Pitié-Salpêtriére Dept. of Genetics and Microorganisms 75651 Paris Cédex 13 University of Lódz France ul. Banacha 12/16 90-127 Lódz Poland vii viii Participants Giovanni Stevanin INSERM U289 Institut Fédératif di Recherche des Neurosciences Cytogénétique et Embryologie Groupe Hospitalier Pitié-Salpêtriére 75651 Paris Cédex 13 France Steve J. Tapscott Division of Human Biology Fred Hutchinson Research Center Seattle, WA 98109 USA Lubov T. Timchenko Section of Cardiovascular Sciences, Departments of Medicine, and Molecular Physiology & Biophysics Baylor College of Medicine Houston, TX 77030 USA CONTENTS 1. MOLECULAR MECHANISMS OF TRS INSTABILITY........................... 1 Pawel Parniewski and Pawel Staczek Introduction ......................................................................................................................... 1 Secondary DNA Structures as a Source of TRS Instability ............................................. 2 Summary ............................................................................................................................ 20 2. MYOTONIC DYSTROPHY: DISCUSSION OF MOLECULAR BASIS ......................................... 27 Lubov T. Timchenko, Steve J. Tapscott, Thomas A. Cooper and Darren G. Monckton DM1 Mutation is an Expansion of CTG Trinucleotide Repeats ................................... 27 Mouse Models of Unstable DNA ...................................................................................... 29 Molecular Pathogenesis of DM1 ....................................................................................... 31 Deficiency of Six5 in DM1 ................................................................................................. 34 Alterations of RNA Metabolism in DM1 ......................................................................... 35 CUGBP1 Targets ............................................................................................................... 39 Other Members of CUGBP1 Family ............................................................................... 39 Conclusions ........................................................................................................................ 40 3. SPINOCEREBELLAR ATAXIAS CAUSED BY POLYGLUTAMINE EXPANSIONS ........................................... 47 Giovanni Stevanin, Alexandra Dürr and Alexis Brice Polyglutamine Expansions as Major Mutations in ADCA ............................................ 49 Age at Onset ....................................................................................................................... 56 Clinical Presentation in Patients ...................................................................................... 56 Neuropathological Lesions ................................................................................................ 59 Factors Influencing Clinical Variability .......................................................................... 61 Physiopathology of Spinocerebellar ataxias Caused by Polyglutamine Expansions ... 61 Conclusions .......................................................................................................................