Trinucleotide Diseases and Instability

176 Pages·1998·6.945 MB·English

by  R. Frank Kooy, Ben A. Oostra, Patrick J. Willems (auth.), Dr. Ben A. Oostra (eds.)

Results and Problems in Cell Differentiation
Series Editors: 21
W. Hennig, 1. Nover, U. Scheer
Springer-Verlag Berlin Heidelberg GmbH
Ben A. Oostra (Ed.)
Trinucleotide
Diseases
and Instability
With 35 Figures
Springer
1~~t;:iY
Dr. Ben A. Oostra
Department of Clinical Genetics
Erasmus University Rotterdam
Molewaterplein 50
3000 DR Rotterdam
The Netherlands
[email protected]
ISBN 978-3-662-22565-3 ISBN 978-3-540-69680-3 (eBook)
DOI 10.1007/978-3-540-69680-3
Library of Congress Cataloging-in-Publication Data
Trinucleotide diseases and instability/Ben A. Oostra, ed.
p. cm. —(Results and problems in cell differentiation; 21)
Includes bibliographical references and index.
ISBN 978-3-662-22565-3
1. Nervous system - Diseases - Genetic aspects. 2. Neurogenetics.
3. Human chromosome abnormalities. I. Oostra, Ben A., 1946-. II. Series.
QH607.R4vol.21
[RC346.4]
571.8'35 s—dc21
[616.8'0442]
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Preface
Till recently, mutations in genes were described in textbooks as deletions or
point mutations. These mutations can be inherited from a parent or they are
de novo alterations.
The discovery in 1991 that human disease can be caused by large-scale ex
pansion of highly unstable trinucleotide repeats has elucidated a new mutation
mechanism, heritable unstable DNA. In the subsequent years more then 10
such disease genes have been identified. All dynamic mutations have been iden
tified in neurological disorders. There are ten possible trinucleotide repeats at
the DNA level, but only 3 have been identified as being involved in human dis
eases. The rather frequent occurence of triplet repeats in the human genome
indicates that other loci subject to unstable expansions may be discovered.
The identification of repeat instability and the identification of disease genes
containing trinucleotide repeats has helped to answer intriguing questions. The
diseases share the unusual characteristic of inheritance with increased disease
severity in successive gernerations, a phenomenon called anticipation. Trinu
cleotide repeat diseases are ideal subjects for direct testing because the muta
tion is almost exclusively of the same type and there is an extremely low occur
ance of new mutations in these diseases. The anticipation can now be explained
by the correlation of increasing repeat length with increased disease serverity.
It can be speculated that other neurological disorders showing anticipation will
be caused by unstable repeats as well.
Since the identification oft he unstable repeats in genes, much effort has been
spent to get an answer to the following questions: What is the mechanism of
the repeat instability? Why are some repeats unstable and others not? What is
the function of the repeats in the (disease) genes? What are the functions of the
(normal) gene products?
The different contributions cover these topics very well. The chapters de
scribe the different groups of trinucleotide repeat genes and the mechanism of
repeat instability. Although we have learned a lot in the last few years, it will be
clear to the readers that there is still more exciting work to do. I hope this book
VI Preface
will encourage them to extend their knowledge further with regard to the
progress in this field.
I am grateful to all the authors in this volume for their hard work and their
excellent contributions.
Rotterdam, January 1998 Ben A. Oostra
Contents
The Fragile X Syndrome and Other Fragile Site Disorders
R. Frank Kooy, Ben A. Oostra, and Patrick J. Willems
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 Fragile Sites .............................................. 3
2.1 Fragile Sites and Disease ................................... 4
2.2 Molecular Base of Fragile Sites .............................. 6
3 Fragile X Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3.1 Phenotype................................................ 9
3.2 Prevalence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3.3 Dynamic Mutation ........................................ 10
3.4 Other Mutations .......................................... 11
3.5 Diagnostics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.6 Fragile X Gene FMRI and Its Protein Product FMRP ........... 16
3.7 Homologous Genes FXR1 and FXR2 ......................... 18
3.8 The Function of FMRP ..................................... 20
3.9 Function of FXR1 and FXR2 ................................ 24
3.10 Repeat Expansion......................................... 25
3.11 Animal Model ............................................ 27
4 FRAXE Mental Retardation ................................. 32
5 Jacobsen Syndrome........................................ 33
6 Conclusion ............................................... 34
6.1 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
6.2 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Molecular Genetics of Huntington's Disease
Marcy E. MacDonald
1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
2 Features of the Disease ..................................... 47
2.1 Clinical Features .......................................... 48
2.2 Neuropathology........................................... 48
2.3 Genetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
3 HD locus ................................................. 49
4 HD Mutation: An Unstable Expanded CAG Repeat............. 51
VIII Contents
4.1 Instability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
4.2 Clinical Correlates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4.3 Preclinical Diagnosis ...................................... 57
5 HD Gene and Its Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
5.1 Huntingtin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
5.2 Evolutionary Conservation ................................. 58
5.3 Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
6 Mechanism of Pathogenesis ................................ 60
6.1 Mutant HD Gene and Its Products...... ........... .......... 60
6.2 Mutant Huntingtin ................... . . . . . . . . . . . . . . . . . . . . . 60
7 Other CAG Repeat Disorders ............................... 61
7.1 Spinal and Bulbar Muscular Atrophy ........................ 61
7.2 Dentatorubral-Pallidolysian Atrophy....... ................. 63
7.3 Spinocerebellar Ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
7.4 A Common Pathogenic Mechanism? . . . . . . . . . . . . . . . . . . . . . . . . . 64
8 Prospects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Myotonic Dystrophy
J. D. Waring and R. G. Korneluk
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
1.1 General Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
1.2 Clinical Features .......................................... 80
2 Genetics and Transmission ............ . . . . . . . . . . . . . . . . . . . . . 82
2.1 Chromosome Analysis and Disease Evolution................. 82
2.2 Predisposing Haplotypes and Mutation Rates ................. 89
2.3 Segregation Distortion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
2.4 Trinucleotide Repeat Mosaicism ............................ 92
2.5 Effect of Sex on Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
3 Gene Structure and Expression.............................. 101
3.1 Gene Structure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
3.2 Transcript Expression ..................................... 103
3.3 Protein Expression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3.4 Protein Structure and Function ............................. 107
4 Consequences of Repeat Expansion............. ............. 110
4.1 Effects on Transcript Levels and Metabolism. . . . . . . . . . . . . . . . . . III
4.2 Effects on Protein Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
4.3 Neighboring Gene Expression and Chromatin Structure. . . . . . . . 115
5 Models.................................................. 117
5.1 Models of Disease ......................................... 117
5.2 Models of Trinucleotide Expansion...................... .... 119
6 Concluding Remarks ...................................... 120
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Contents IX
Instabilities of Triplet Repeats: Factors and Mechanisms
Robert D. Wells, Albino Bacolla, and Richard P. Bowater
1 Genetic Instabilities of Repetitive DNA and Human Diseases.... 133
1.1 Diseases Associated with Expansion of Triplet Repeat Sequences 134
1.2 Microsatellite Instability and Cancer .. . . . . . . . . . . . . . . . . . . . . . . . 138
2 Instabilities in a Genetically Defined Bacterial System. . . . . . . . .. 140
2.1 General Comments on CTG·CAG ............................ 140
2.2 Preferential Expansion of CTG·CAG ......................... 143
2.3 Site of Expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 143
2.4 Mismatch Repair.......................................... 144
2.5 Fragile X CGG·CCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2.6 DNA Polymerase Pausing .................................. 147
2.7 Molecular Similarities Between Humans and Escherichia coli ... 149
2.8 Summary of Factors Influencing Genetic Instability. . . . . . . . . . .. 150
3 Flexible and Writhed CTG·CAG and CGG·CCG ................ 150
3.1 Flexibility of DNA and General Biological Processes. . . . . . . . . . . . 151
3.2 Determination of DNA Flexibility............................ 152
3.3 Bending and Twisting Forces of (CTG·CAG)n and (CGG·CCG)n . 153
3.3.1 Theory of Ring Closure.. . .. .. . . .. . . . .. . . .. . .. .. . .. . . .. . . ... 153
3.3.2 Cyclization Kinetics on DNA Fragments Containing (CTG·CAG)n
and (CGG·CCG)n .......................................... 155
3.4 DNA Flexibility as a Source of Genetic Instability. . . . . . . . . . . . .. 156
4 Prospects for the Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 158
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 159
Subject Index...................................................... 167