Preface

The historic discoveries in 1991 that fragile X syndrome (FXS) is caused by dynamic expansion of a d(CGG) trinucleotide repeat sequence in the 5'-UTR region of the FMR1 gene (Fu et al. 1991, Oberlé et al. 1991, Pieretti et al. 1991, Verkerk et al. 1991, Yu et al. 1991) and that Spinal and Bulbar Muscular Atrophy (SBMA) results from a d(CAG) expansion in the androgen receptor gene (LaSpada et al. 1991), launched a broad new area of human molecular genetics. It was soon appreciated that many repeats at different loci in the human genome are subject to dynamic expansion and that this novel type of mutation results in a diverse class of neurological, neuromuscular and neurodegenerative disorders known as the Nucleotide Expansion Disorders or Repeat Expansion Disorders. While many disorders can be caused by changes in the size of a nucleotide or amino acid repeat tract (Pearson, Edamura and Cleary 2005), some of these repeat tracts are meiotically stable. To date only 20 or so disorders are attributable to dynamic mutations such as those responsible for FXS and SBMA, and it is these disorders that are the subject of this book.

Efforts of many research teams world-wide have led to the identification of the genes affected by nucleotide repeat expansions. In parallel, advances have been made in elucidating the underlying molecular mechanisms ofrepeat expansions and the pathological consequences of these mutations. The insights gained into the molecular, cellular and organismal bases of some disorders have already generated initial ideas and experimental approaches to their therapy (Di Prospero and Fischbeck 2005).

Unlike static mutations that are stably transmitted, nucleotide repeats are dynamically expanded both upon transmission to offspring and in some instances also within different tissues of an individual. Longer repeat stretches are more prone to expansion than shorter tracts and, in most cases where the disease is not congenital, repeat length is correlated with an earlier age of onset and an increased disease severity. As a result, the expansion disorders are characterized by genetic anticipation in which each successive generation presents a more severe form of the disease.

Different disorders are characterized by differences in the sequence and length of the nucleotide repeat unit as well as by its location within the gene. The largest number of disorders is linked to expansion of trinucleotide re peat sequences. Fewer diseases are associated with expansions of four, five or 12 nucleotide repeat sequences (Table 1). The location of expanded repeats within or outside coding regions of genes is arguably their most instructive characteristic - indicative of a likely pathological mechanism of the disease. As schematically shown in Fig. 1, several disorders are linked to the expansion of different repeats in the promoter, the 5' or 3' untranslated regions or in introns of various genes. A different class of diseases is coupled to expansions of repeat tracts in exon sequences. The largest group within this class is associated with expansion of d(CAG) triplet repeat sequences that results in the accumulation of product proteins with abnormally long polyglutamine tracts.

Identification of affected genes, the location of the position of expanded tracts outside or within the coding regions of the genes and characterization of their protein products, has shed light in many cases on the resulting pathologies. Expansions can result in either a loss-of-gene function or a gain-of-function. Loss-of-function mutations result in reduced or abolished protein function. Gain-of-function mutations confer abnormal properties on the protein or mRNA. Most, if not all, of the expansion mutations occurring in coding regions of genes result in a gain-of-function, while many expansions in non-coding regions result in a loss-of-function. Although the underlying mechanism of a number of nucleotide expansion disorders is still unknown, those diseases that were characterized as being associated with loss- or gain-of-function, opened new vistas into the diverse pathological processes that are at the basis of repeat expansion disorders. Thus, some disorders develop as a result of gene silencing (i.e. fragile X syndrome), others are due to aberrant protein function (polyglutamine disorders such as Huntington and a large number of Spinocerebellar ataxias), whereas another set of disorders results

The SCA8 associated repeat is located in a transcribed region of the SCA8 gene that has no open reading frame.

The locations of the repeats in SCA12 and HDL2 are still uncertain.

The SCA8 associated repeat is located in a transcribed region of the SCA8 gene that has no open reading frame.

The locations of the repeats in SCA12 and HDL2 are still uncertain.

Fig. 1 Location of disorder-associated expandable nucleotide repeats. Schematically shown are locations of disease-causing nucleotide repeats and their location within coding or non-coding regions of affected genes. The repeat unit sequences are of the DNA strands that are considered to be relevant to the pathology of each disorder

Table 1 Expanded nucleotide repeat disorders. Listed are major disorders that are reviewed in this volume. A comprehensive catalogue of all the repeat expansions described to date, including those with no confirmed disorder linkage can be found elsewhere (Pearson, Edamura and Cleary, 2005). The listed repeat unit sequences are those of the DNA strands that are thought to be relevant to the pathology of the respective disorders. a HD- Huntington disease; SCA - Spinocerebellar ataxia; SBMA-Spinal and Bulbar Muscular Atrophy; DRPLA-Dentatorubral-pallidoluysian atrophy; HDL2 - Huntington disease-like 2; DM1 - Myotonic dystrophy type 1; FRDA - Friedreich ataxia; FXS, Fragile X Syndrome, FRAXE MR, FRAXE mental retardation; DM2 - Myotonic dystrophy type 2; EPM1 - Progressive Myoclonus Epilepsy.c Nucleotide repeats expanded in coding regions. d Nucleotide repeats expanded in non-coding regions. *the relevant strand has not been definitively determined

Table 1 Expanded nucleotide repeat disorders. Listed are major disorders that are reviewed in this volume. A comprehensive catalogue of all the repeat expansions described to date, including those with no confirmed disorder linkage can be found elsewhere (Pearson, Edamura and Cleary, 2005). The listed repeat unit sequences are those of the DNA strands that are thought to be relevant to the pathology of the respective disorders. a HD- Huntington disease; SCA - Spinocerebellar ataxia; SBMA-Spinal and Bulbar Muscular Atrophy; DRPLA-Dentatorubral-pallidoluysian atrophy; HDL2 - Huntington disease-like 2; DM1 - Myotonic dystrophy type 1; FRDA - Friedreich ataxia; FXS, Fragile X Syndrome, FRAXE MR, FRAXE mental retardation; DM2 - Myotonic dystrophy type 2; EPM1 - Progressive Myoclonus Epilepsy.c Nucleotide repeats expanded in coding regions. d Nucleotide repeats expanded in non-coding regions. *the relevant strand has not been definitively determined

REPEAT SIZE

REPEAT UNIT

DISORDERa

AFFECTED GENEb

PATHOGENESIS

Trinucleotide

d(CAG)n

HD

Huntingtinc

GOF

SBMA

Androgen receptor

GOF

DRPLA

DRPLA (or atrophin 1)

GOF

SCA1

Ataxin-lc

GOF

SCA2

Ataxin-2C

GOF

SCA3

Ataxin-3C

GOF

SCA6

Ca2+ channel a, 1A subunitc

?

SCA7

Ataxin-7C

GOF

SCA17

TATA box binding proteinc

GOF

SCA12

PPP2R2B

?

d(CTG)n

DM1

Dystrophia myotonia Protein kinased

GOF (+LOF in CDM1?)

SCA8

SCA8d

?

HDL2*

Junctophilin-3

?

d(GAA)

FRDA

Frataxind

LOF

d(CGG)n

FXS

FMRld

GOF (RNA)/LOF

d(CCG)

FRAXE MR 0

FMR2d

LOF

Tetranucleotide

d(CCTG)n

DM2

Zinc finger protein 9d

GOF (RNA)

Pentanucleotide

d(ATTCT)n

SCA10

Ataxin-10d

?

Dodecanucleotide

d(CCCCGCCCCGCG)

EPM1

Cystatin B

LOF

from RNA toxicity (Myotonic dystrophies types 1 and 2 and possibly additional nucleotide expansion diseases).

This volume presents an updated survey of the current knowledge on a number of human nucleotide repeat expansion disorders. It is not, however, a comprehensive compilation of every known disease. Rather, the different chapters review well defined disorders whose mechanism is either already understood or is close to being elucidated. We were fortunate indeed to have leading researchers contribute chapters on the state-of-the-art of their respective areas of expertise. The different chapters cover nearly every aspect of major human nucleotide repeat expansion disorders including the molecular mechanisms of expansion, the mode of inheritance of the individual diseases and discussion of their clinical presentation, pathological mechanisms, animal models and prospective therapeutic strategies.

A volume on a group of highly divergent disorders and their different molecular and cellular mechanisms can, of course, be organized according to different criteria. We chose to dedicate one section to the general molecular mechanisms of repeat expansion and then to group different diseases in separate sections based on whether the repeat occurs in non-coding or coding regions of the affected gene. The last chapter is devoted to diseases whose location in the affected gene is as yet unresolved. Thus, the opening section of this volume consists of a comprehensive survey by R. R. Sinden and M. J. Pytlos (Texas A&M University) of the current understanding of the varied types of secondary structures of repeat DNA tracts and their roles in expansion. The second section is dedicated to disorders that result from expansion of repeat sequences in non-coding regions. Expert authors review the divergent cases of Fragile X syndrome (F. Tassone and P. J. Hagerman, University of California, Davis), FRAXE MR (D. L. Nelson, Baylor College of Medicine), Friedreich Ataxia (M. Pandolfo, Université Libre, Brussels), Progressive My-oclonus Epilepsy (M. D. Lalioti, S. E. Antonarakis and H. S. Scott, Yale and Geneva Universities and Walter and Eliza Hall Institute, Australia) Myotonic dystrophies 1 and 2 (P. Teng-umnuay and M. S. Swanson, University of Florida, Gainsville) and Spinocerebellar ataxia 10 (X. Lin and T. Ashizawa, University of Texas, Galvston). The third section is devoted to disorders that are linked to repeat expansion in protein-encoding regions of genes. Included is a review on the large body of data that is now available on the diverse group of polyg-lutamine expansion disorders, (M. J. Friedman, S.-H. Li and X.-J. Li, Emory University). Also in this section, M. Frontali (Institute of Neurobiology and Medicine, Rome) discusses Spinocerebellar ataxia 6 and the unresolved issue of its pathological mechanism. The fourth section deals with expansion disorders whose precise mechanisms are still under investigation This part consists of surveys of our current understanding of Spinocerebellar ataxia 8 (K. A. Dick, J. W. Day, and L. P. W. Ranum, University of Minesota) and of Spinocerebellar ataxia 12 and Huntington disease like 2 (R. L. Margolis, S. E. Holmes, E. O'Hearn, D. D. Rudnicki, J. Hwang, N. Cortez-Aperza, O. Plenikova and J. C.

Troncoso, Johns Hopkins University). In a final postscript we briefly summarize the main unanswered questions concerning the molecular mechanisms of the nucleotide repeat disorders and point to future directions of research.

Many individuals made the publication of this book possible. First and foremost, we are thankful to the authors of the different chapters for their comprehensive and lucid reviews. We are grateful to the series editor, Professor H. J. Gross for recognizing the importance of the subject matter of this book, for initiating its compilation and for his steady support. Last, but not least, we gratefully acknowledge the contribution of Ursula Gramm, Editor Springer Life Sciences whose dedicated work was vital in bringing the volume to press.

Haifa, Michael Fry

Bethesda, Karen Usdin

June 2006

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