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 66

TowardsTherapy 67

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4. SPINOCEREBELLAR ATAXIA TYPE 10:

A DISEASE CAUSED BY A LARGE ATTCT

REPEAT EXPANSION 79

Tohru Matsuura and Tetsuo Ashizawa

Introduction 79

Clinical Features 81

Identification of the SCA10 Mutation 82

Prospects of Research 86

5. THE MOLECULAR BASIS OF FRIEDREICH ATAXIA 99

Massimo Pandolfo

Gene Structure and Expression 101

Point Mutations 107

Frataxin Structure and Function 108

Current Hypotheses for the Pathogenesis of Friedrich Ataxia 111

Approaches for Treatment 113

INDEX 119

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