Bates Gillian P, Hay David G
Department of Medical and Molecular Genetics, GKT School of Medicine, King's College, Guy's Hospital, London, UK.
Methods Mol Biol. 2004;277:3-15. doi: 10.1385/1-59259-804-8:003.
Since their discovery in 1991, triplet repeat mutations have been found to be the cause of genomic fragile sites, two of which are linked to mental retardation, myotonic dystrophy, and several late-onset neurodegenerative diseases. In all cases, these mutations exhibit gametic and/or somatic instability once they have expanded into the mutant range. The mutations are located in coding and noncoding gene regions and have been found to act by dominant and recessive mechanisms. A wide range of mouse models has been generated to understand both of the mechanisms that underlie repeat instability and the molecular pathogenesis of the diseases. Mouse models have proved extremely useful in these goals and are now also being used for the preclinical testing of therapeutic compounds. This chapter reviews the successes and limitations of the approaches that have been developed.
自1991年被发现以来，三联体重复突变已被证实是基因组脆性位点的成因，其中两种与智力迟钝、强直性肌营养不良以及几种迟发性神经退行性疾病有关。在所有这些病例中，这些突变一旦扩展到突变范围，就会表现出配子和/或体细胞不稳定性。这些突变位于编码和非编码基因区域，并且已发现它们通过显性和隐性机制起作用。为了了解重复序列不稳定性的潜在机制以及这些疾病的分子发病机制，已经构建了多种小鼠模型。事实证明，小鼠模型在实现这些目标方面极为有用，目前也正被用于治疗性化合物的临床前测试。本章回顾了已开发方法的成功之处和局限性。
