ebook img

The Molecular Biology of Neurological Disease PDF

270 Pages·1988·26.511 MB·English
Save to my drive
Quick download
Download
Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.

Preview The Molecular Biology of Neurological Disease

Butterworths International Medical Reviews Neurology 9 Published titles 1 Clinical Neurophysiology Erik Stälberg and Robert R. Young 2 Movement Disorders C. David Marsden and Stanley Fahn 3 Cerebral Vascular Disease Michael J. G. Harrison and Mark L. Dyken 4 Peripheral Nerve Disorders Arthur K. Asbury and R. W. Gilliatt 5 The Epilepsies Roger J. Porter and Paolo L. Morselli 6 Multiple Sclerosis W. I. McDonald and Donald H. Silberberg 7 Movement Disorders 2 C. David Marsden and Stanley Fahn 8 Infections of the Nervous System Peter G. E. Kennedy and Richard T. Johnson The Molecular Biology of Neurological Disease Edited by Roger N. Rosenberg, MD Professor of Neurology and Physiology; Chairman, Department of Neurology, University of Texas Southwestern Medical Center, Southwestern Medical School, Dallas, Texas, USA and A. E. Harding, MD, MRCP Reader in Clinical Neurology at the Institute of Neurology; Consultant Neurologist at the National Hospitals for Nervous Diseases, London, UK Butterworths London Boston Singapore Sydney Toronto Wellington All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, including photocopying and recording, without the written permission of the copyright holder, application for which should be addressed to the Publishers. Such written permission must also be obtained before any part of this publication is stored in a retrieval system of any nature. This book is sold subject to the Standard Conditions of Sale of Net Books and may not be re-sold in the UK below the net price given by the Publishers in their current price list. First published, 1988 © Butterworth & Co. (Publishers) Ltd, 1988 British Library Cataloguing in Publication Data The Molecular biology of neurological disease. - (Butterworths international medical reviews. Neurology; ISSN 0206-0137). 1. Nervous system-Diseases 2. Pathology, Molecular I. Rosenberg, Roger N. II. Harding, A. E. 616.8 RC347 ISBN 0-407-02400-X Library of Congress Cataloging-in-Publication Data The Molecular biology of neurological disease/edited by Roger N. Rosenberg and A. E. Harding. p. cm. - (Butterworths international medical reviews. Neurology) Includes bibliographies and index. ISBN 0-407-02400-X 1. Nervous system-Disease-Pathophysiology. 2. Molecular neurobiology. I. Rosenberg, Roger N. II. Harding, A. E. III. Series. [DNLM: 1. Gene Expression Regulation. 2. Molecular Biology. 3. Nervous System Disease-familial. WL 100 M7186] RC346.M639 1988 616.8'047-dcl9 DNLM/DLC 87-35478 for Library of Congress CIP Photoset by Butterworths Litho Preparation Department Printed and bound by Robert Hartnoll (1985) Ltd, Bodmin, Cornwall Foreword For almost a quarter of a century (1951-1975), subjects of topical interest were written about in the periodic volumes of our predecessor, Modern Trends in Neurology. Although both that series and its highly regarded editor, Dr Denis Williams, are now retired, the legacy continues in the present Butterworths series in Neurology. As was the case with Modern Trends, the current volumes are intended for use by physicians who grapple with the problems of neurological disorders on a daily basis, be they neurologists, neurologists in training, or those in related fields such as neurosurgery, internal medicine, psychiatry, and rehabilita­ tion medicine. Our purpose is to produce annually a monograph on a topic in clinical neurology in which progress through research has brought about new concepts of patient management. The subject of each monograph is selected by the Series Editors using two criteria: first, that there has been significant advance in knowledge in that area and, second, that such advances have been incorported into new ways of managing patients with the disorders in question. This has been the guiding spirit behind each volume, and we expect it to continue. In effect we emphasize research, both in the clinic and in the experimental laboratory, but principally to the extent that it changes our collective attitudes and practices in caring for those who are neurologically afflicted. C. D. Marsden A. K. Asbury Series Editors v Preface The 'guiding spirit' behind each of the volumes in the Butterworths series of neurological reviews is to focus on topics in which progress through research has altered the management of patients with neurological disease. In a field festooned with verbal hyperbole, it seems feeble to state that advances in molecular biology will revolutionize the practice of medicine, including neurology, over the next few years. The revolution has begun, and it is important that those who look after neurological patients are aware of it. This book is designed to review recent advances in our understanding of the molecular mechanisms of neurological disease, and immediate and future applications of molecular biological techniques to clinical practice. We hope that it will be of value to neuroscientists in general, but particularly to established clinicians and those in training. We wish to thank the authors for their excellent contributions, and two more tangible guiding spirits, David Marsden and Art Asbury, for asking us to edit this volume. Roger N. Rosenberg Anita Harding Vll Contributors Alastair Compston, PhD, FRCP Professor of Neurology, University of Wales College of Medicine, Cardiff, UK Fred Gilbert, MD Associate Professor of Medical Genetics and Pediatrics, Division of Medical Genetics, Mt Sinai School of Medicine, New York, USA T. Conrad Gilliam Departments of Psychiatry and Neurology, College of Physicians and Surgeons, Columbia University, New York, USA Michel Goedert, MD,PhD Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge, UK Sue Griffin, PhD Professor, Departments of Pediatrics and Anatomy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Abraham Grossman Research Assistant Professor of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA James F. Gusella, PhD Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA William E. Hahn, PhD Professor, Department of Cellular and Structural Biology, University of Colorado School of Medicine, Denver, Colorado, USA A. E. Harding, MD,MRCP Reader in Clinical Neurology at the Institute of Neurology; Consultant Neurologist at the National Hospitals for Nervous Diseases, London, UK IX x Contributors Peter S. Harper Professor and Consultant in Medical Genetics, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UK IanJ. Holt, BSC Research Assistant, Department of Clinical Neurology, Institute of Neurology, London, UK Ruth F. Itzhaki, MSC, PhD, MA Honorary Reader in Cell Biology, UMIST, Manchester, UK Albee Messing, VMD, PhD Assistant Professor of Neuropathology, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, USA Girish Modi, MB, BCh, MSC, PhD Assistant Professor, Department of Neurology, University of Natal, Durban, South Africa Marcelle R. Morrison, PhD Associate Professor, Departments of Neurology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA Gregory P. Owens, PhD Postdoctoral Fellow, Department of Cellular and Structural Biology, University of Colorado School of Medicine, Denver, Colorado, USA David Pleasure, MD Professor of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA Roger N. Rosenberg, MD Professor of Neurology and Physiology and Chairman, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Robert S. Sparkes, MD Professor of Medicine, UCLA School of Medicine, Los Angeles, California, USA R. J. Swingler, BSC,MRCP(UK) Lecturer in Neurology, University of Edinburgh, Edinburgh, UK Kenneth L. Tyler, MD Assistant Professor, Departments of Neurology and Microbiology and Molecular Genetics, Harvard Medical School; Assistant Neurologist, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Frank S. Walsh, BSC, PhD Wellcome Trust Senior Lecturer, Department of Neurochemistry, Institute of Neurology, Queen Square, London, UK 1 Molecular genetics and neurological disease: basic principles and methods A. E. Harding and Roger N. Rosenberg INTRODUCTION Prenatal diagnosis of a genetic disease, α-thalassaemia, was first performed using molecular genetic techniques 23 years after the description of the double helical structure of deoxyribonucleic acid (DNA) by Watson and Crick in 1953 (Watson and Crick, 1953; Kan, Golbus and Dozy, 1976). Subsequently, rapid progress has been made in elucidating the molecular basis of inherited disease. At least 3000 disorders exhibiting mendelian inheritance are known to occur in man; 936 of these had been localized to specific chromosomal regions, many using molecular genetic techniques, by 1986 as compared to 300 in 1975 (McKusick, 1986). The molecular genetics of a number of inherited neurological disorders will be discussed in detail in the Chapters 10 to 18. The 'new genetics' also has many applications in other neurological and neurobiological problems, including oncology, virology, and development; selected topics pertaining to these are dealt with in Chapters 2-9. For the clinician or scientist without a strong background in cell biology or genetics, understanding recombinant DNA technology is hampered not only by lack of familiarity with the techniques and their application, but also by the jargon which has been generated by this rapidly expanding field. It is hoped that this chapter will provide a general introduction and glossary to the more specific topics covered by the rest of the book. Many advances in neurogenetics have been made using molecular genetic techniques in genetic linkage studies; this topic will be discussed in some detail, partly for illustrative purposes but also because of its immediate clinical relevance. PRINCIPLES OF MENDELIAN INHERITANCE Every human cell contains a pair of each of 22 chromosomes called the autosomes. In addition there are either two X chromosomes or one X and one Y chromosome, depending on the sex of the individual. During cell division the process of mitosis results in two daughter cells which are diploid, that is, each contains an identical chromosomal complement to the parent cell. Gametogenesis involves the more complex process of meiosis, during which each pair of chromosomes exchanges 1 2 Molecular genetics and neurological disease: basic principles and methods genetic material, resulting in gametes which are haploid, containing only half the number of chromosomes of the parent cell. Defective genes on the autosomes (chromosomes 1-22) may be inherited as dominant or recessive traits. An individual affected by an autosomal dominant disorder has a 50% chance of transmitting it to offspring (Figure 1.1). In this case, a heterozygous gene carrier manifests the disease despite the presence of a normal corresponding gene (allele) on the other half of the chromosome pair. 6TÜ Ill % Figure 1.1 Pedigrees illustrating (a) autosomal dominant; (b) autosomal recessive; and (c) X-linked inheritance. Square = male; circle = female; filled symbol = affected; open symbol = unaffected; Θ in (c) indicates obligate carrier This is not so in autosomal recessive inheritance, where it is necessary for both alleles to be abnormal in order for the disease to be expressed (see Figure 1.1), that is, the affected individual is homozygous. We are all heterozygous for one or two recessive genes; the commonest autosomal recessive disorder in the United Kingdom is cystic fibrosis, and about 5% of the population carry the cystic fibrosis gene (Harper, 1981). If two heterozygotes for the same autosomal recessive gene mate, on average one in four of their children will be affected, two out of four will be carriers and one out of four will not carry the gene. It should be obvious that, in populations where family size is small, the majority of individuals with autosomal recessive disorders do not have affected sibs, and often the clinician does not suspect the presence of a genetically determined disorder. Autosomal recessive disorders are more common amongst the offspring of consanguineous parents, for example cousins, as these are more likely to share autosomal recessive genes in common than unrelated members of the population. Structure and function of nucleic acids 3 Defective genes on the X chromosomes show a distinctive pattern of inheritance in which males are most severely affected, and females carrying the gene may be moderately or mildly affected or clinically normal. The variation in expression of an X-linked disorder in females is due to the process of lyonization, during which the expression of one X chromosome is suppressed randomly in each cell. The distinction between X-linked recessive (in which female carriers are normal) and X-linked dominant (female carriers affected) disorders is rather artificial, although these terms are often used. An important feature of X-linked inheritance is that male-to-male transmission never occurs (see Figure 1.1), but all the female offspring of affected males inherit the abnormal gene. STRUCTURE AND FUNCTION OF NUCLEIC ACIDS Both DNA and ribonucleic acid (RNA) consist of sequences of nucleotides, each of which contain a pentose sugar, a phosphate group, and a nitrogenous base. The last may be either pyrimidines (uracil, cytosine, and thymine), or purines (adenine and guanine). DNA contains adenine (A), guanine (G), thymine (T), and cytosine (C) (Figure 1.2). In RNA uracil (U) replaces thymine. RNA is usually single-stranded, but DNA is generally double-stranded, forming an antiparallel double helix; G and C always pair together by means of hydrogen bonds and the same applies to A and T. Compact mammalian chromosomal DNA is supercoiled around proteins called histones. The human genome, that is all the chromosomal DNA, consists of about 3 x 109 base pairs (bp) of DNA. 3ΌΗ 5'P Figure 1.2 The structure of deoxyribonucleic acid. P = phosphate; D = deoxyribose; H = hydrogen; A = adenine; C = cytosine; G = guanine; T = thymine; OH = hydroxyl group. Dotted lines indicate hydrogen bonds between paired nucleotides

See more

The list of books you might like

Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.