Book contents
- Frontmatter
- Contents
- List of contributors
- Preface
- Acknowledgments
- Foreword by Sid Gilman
- PART I INTRODUCTION
- PART II THEORIES OF CEREBELLAR CONTROL
- PART III CLINICAL SIGNS AND PATHOPHYSIOLOGICAL CORRELATIONS
- PART IV SPORADIC DISEASES
- PART V TOXIC AGENTS
- PART VI ADVANCES IN GRAFTS
- PART VII NEUROPATHOLOGY
- PART VIII DOMINANTLY INHERITED PROGRESSIVE ATAXIAS
- 26 Spinocerebellar ataxia type 1
- 27 Spinocerebellar ataxia type 2
- 28 Spinocerebellar ataxia type 3
- 29 Spinocerebellar ataxia type 4
- 30 Spinocerebellar ataxia type 5
- 31 Spinocerebellar ataxia type 6
- 32 Autosomal dominant cerebellar ataxia with progressive pigmentary macular dystrophy
- 33 Spinocerebellar ataxia type 8
- 34 Dentatorubral-pallidoluysian atrophy
- 35 Molecular mechanisms of triplet repeat expansions in ataxias
- PART IX RECESSIVE ATAXIAS
- Index
35 - Molecular mechanisms of triplet repeat expansions in ataxias
from PART VIII - DOMINANTLY INHERITED PROGRESSIVE ATAXIAS
Published online by Cambridge University Press: 06 July 2010
- Frontmatter
- Contents
- List of contributors
- Preface
- Acknowledgments
- Foreword by Sid Gilman
- PART I INTRODUCTION
- PART II THEORIES OF CEREBELLAR CONTROL
- PART III CLINICAL SIGNS AND PATHOPHYSIOLOGICAL CORRELATIONS
- PART IV SPORADIC DISEASES
- PART V TOXIC AGENTS
- PART VI ADVANCES IN GRAFTS
- PART VII NEUROPATHOLOGY
- PART VIII DOMINANTLY INHERITED PROGRESSIVE ATAXIAS
- 26 Spinocerebellar ataxia type 1
- 27 Spinocerebellar ataxia type 2
- 28 Spinocerebellar ataxia type 3
- 29 Spinocerebellar ataxia type 4
- 30 Spinocerebellar ataxia type 5
- 31 Spinocerebellar ataxia type 6
- 32 Autosomal dominant cerebellar ataxia with progressive pigmentary macular dystrophy
- 33 Spinocerebellar ataxia type 8
- 34 Dentatorubral-pallidoluysian atrophy
- 35 Molecular mechanisms of triplet repeat expansions in ataxias
- PART IX RECESSIVE ATAXIAS
- Index
Summary
Introduction
Expansions of specific DNA triplet repeats are an initial step in the etiology of a number of ataxias in humans. In some diseases, such as spinocerebellar ataxia 1 (SCA1), SCA2, SCA3, and Machado–Joseph disease, the repetitive DNA sequences are translated into long tracts of polyglutamine, which alters the interactions of the target protein with cellular constituents and leads to the development of disease. For other disorders, including SCA8, the DNA repeat is located in a non-coding region of transcribed sequences and disease is probably caused by altered gene expression. In studies in lower organisms, mammalian cells, and transgenic mice, high frequencies of length changes (increases and decreases) occur in long DNA triplet repeats. A variety of processes acting on DNA influences the genetic stability of DNA triplet repeats, including replication, recombination, repair, and transcription. It is not yet known how these different multi-enzyme systems interact to produce the genetic mutation of expanded repeats. In-vitro studies have shown that DNA triplet repeats can adopt several unusual DNA structures, including hairpins, triplexes, sticky DNA, quadruplexes, slippedstructures, and highly flexible and writhed helices. The formation of stable, unusual structures within the cell is likely to disturb DNA metabolism and be a critical factor in the molecular mechanism(s) leading to genetic instabilities of DNA repeats and, hence, to disease pathogenesis.
During the 1990s, unusual mutation events that produce expansion of DNA triplet repeats were identified as the cause of several hereditary neurological disorders. The association of length changes within repetitive DNA tracts in human diseases has stimulated interest in these sequences, as illustrated by recent authoritative books (Wells and Warren, 1998; Oostra, 1998; Rubinsztein and Hayden, 1998).
- Type
- Chapter
- Information
- The Cerebellum and its Disorders , pp. 491 - 502Publisher: Cambridge University PressPrint publication year: 2001