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Figure 7.8 Unstable repeat expansions and human disease. Overview of unstable repeat disorders classified based on knowledge of pathogenic mechanism. Adapted and reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Genetics (Gatchel and Zoghbi 2005), copyright 2005; and with permission from Orr and Zoghbi (2007).

onset, a phenomenon described as genetic anticipation (Howeler et al. 1989). In myotonic dystrophy (see Box 7.15), for example, early observations by Greenfield (1911) and Fleischer (1918) described how among successive generations of affected families, disease manifestations included progressively earlier onset of cataracts, with later generations manifesting classical myotonic dystrophy with muscle weakness and presenile cataracts, and increasingly severe symptoms, mental retardation, infertility, and a high infant mortality rate. These observations were confirmed in later family studies (Howeler et al. 1989) and the molecular genetic basis for anticipation in this disease found to relate to dramatic expansions of a CTG repeat (Buxton et al. 1992).

In the following sections, some of the different disorders resulting from unstable repeat expansions are described to illustrate common themes in pathogenesis and specific mechanisms responsible for disease. In noncoding DNA, the expansion of unstable repeats may reduce gene expression resulting in loss of function as seen in fragile X syndrome (see Box 7.8) and Friedreich's ataxia (see Box 7.10); in transcribed but not translated DNA sequences disease may result through RNA-mediated mechanisms as seen with myotonic dystrophy (see Box 7.15). Expansions of unstable repeats in coding DNA sequence is seen with CAG trinucleotide repeats leading to polyglutamine diseases such as Huntington's disease through changes in protein conformation, with neuronal degeneration and loss (Fig. 7.8; Section 7.6.2). Other coding sequence trinucleotide repeat insertions and deletions may result in disease, notably GCG repeats encoding alanine resulting in rare congenital developmental and neuromuscular disorders through protein misfolding, aggregation, and degradation (Fig. 7.9) (Albrecht and Mundlos 2005). Such GCG expansions are, however, small and show low levels of polymorphism: the repeats are stable at meiosis or mitosis rather than dynamic, and are thought to arise mainly due to non-allelic homologous recombination at meiosis (Warren 1997).

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