DIRECT Technologies for Molecular Cloning of Genes Containing Expanded CAG Repeats

Expansions of unstable CAG/CTG trinucleotide repeats have been identified as a common pathogenic mechanism in a growing number of hereditary neurodegenerative diseases, including myotonic dystrophy, spinal and bulbar muscular atrophy, Huntington’s disease (HD), spinocerebellar ataxia type 1 (SCA1), dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), SCA2, SCA6, SCA7, SCA8, SCA12, and SCA17 (reviewed in refs. 1 –7 ). From the viewpoint of clinical genetics, these diseases are characterized by anticipation, i.e., accelerating age at onset and increasing disease severity in successive generations. It has been discovered that anticipation is a result of intergenerational increase in the size of expanded CAG repeats. These observations suggest that many hereditary neurodegenerative diseases characterized by anticipation and the broad spectrum of the clinical presentations are likely to be caused by the unstable expansion of CAG repeats.