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23 DNA Replication, Repeat Instability, and Human Disease

John D. Cleary, Christopher E. Pearson, Albert R. La Spada


Alterations in the size of simple repetitive sequences, mostly CNG (where N = A, C, T, or G), within specific human genes comprise the disease-causing mutation for a growing class of inherited neurological, neurodegenerative, and neuromuscular disorders (Fig. 1). At least 36 human disorders are attributed to repeat instability, including Huntington’s disease (HD), myotonic dystrophy type 1 (DM1), and fragile X mental retardation syndrome (FRAXA) (see Appendix, Table VI). Depending on the disorder, repeat instability can be observed in somatic and germ-line tissues for both nonproliferative and proliferative cells, suggesting that a variety of DNA metabolic processes underlie the mutational process. Evidence indicates that DNA replication, independently and in conjunction with other metabolic processes, actively contributes to repeat instability. The contributions of DNA repair, features of instability in patients, and disease pathogenesis have been reviewed elsewhere (Cleary and Pearson 2003; Gatchel and Zoghbi 2005; Pearson et al. 2005). This chapter focuses on the contribution of DNA replication to repeat instability, primarily for trinucleotide repeats (TNRs).

TNR instability is a “dynamic mutation” (Richards and Sutherland 1992) caused by the increased propensity of the expanded product of a mutation to undergo further expansion mutation. Within the general population, TNR tracts are typically short, polymorphic, and stably transmitted, only becoming unstable above a stability threshold length, usually 34–45 repeats. Transmission (and subsequent expansion) of the expanded repeat tract across multiple generations results in genetic anticipation, a decrease in age of onset, and increase in disease severity that is characteristic of...

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