The Molecular Biology of Neurological Disease

270 Pages·1988·26.511 MB·English

by  Roger N. Rosenberg and A. E. Harding (Eds.)

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
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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