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© 2009 Nova Science Publishers, Inc. Microsatellites are abundant repetitive sequences accounting for 3% of the human genome. The list of diseases that are triggered by the unstable expansion of some of these sequences continues to increase, and includes disorders such as Huntington's Disease or Fragile X Syndrome. Diseases of unstable repeat expansion share peculiar genetic features. The size of the repetitive array correlates with the severity and the age of onset of the disease. Moreover, the microsatellite has a strong tendency to expand promoting earlier and more severe expression of the disease in successive generations. The most important factors determining this repeat instability seem to be related to structural properties. After DNA slippage, the more stable non-B DNA conformations serve as substrates for DNA repair and might therefore be excised. In contrast, some non-B DNA conformations could avoid the DNA repair systems. Furthermore, a recent study suggests the recruitment of microsatellites by genes that encode transcription factors and other regulatory genes, particularly in the nervous system. Therefore, some of these repeat polymorphisms may be associated with phenotypic traits that have the potential to increase fitness, but also susceptibility to unstable expansion diseases. The general pathogenic mechanisms involve altered protein function or aberrant RNA-protein interactions. Therapeutic strategies target the protein or counteract cellular defects reversing metabolic abnormalities. Additionally, gene therapy holds great promise hampering allele expansion or reducing the expression of the expanded allele using small interfering RNAs or viral-mediated approaches. Although much effort has been devoted to understanding the full disease process and the development of an effective therapy, many aspects of these disorders still remain to be fully understood and are addressed in this chapter.



Book title

The Human Genome: Features, Variations and Genetic Disorders

Publication Date



197 - 211