Transgenic Mouse Models of CAG Trinucleotide Repeat Neurologic Diseases

Abstract

During the past few years a new class of mutation has burst upon the human genetics scene, resulting in a rethinking of some basic principles of Mendelian genetics. This form of mutation, termed unstable trinucleotide repeats, is a dynamic mutation that is produced by heritable unstable DNA. For reasons not understood, these dynamic mutations seem to effect predominately genes whose function is critical for neuromuscular tissue. To date 12 diseases have been characterized as caused by the expansion of an unstable trinucleotide repeat.Among these are fragile XA (Kremer et al., 1991; Verkerk et al., 1991; Yu et al., 1991) and fragile XE (Knight et al., 1993) syndromes, myotonic dystrophy(Brook et al., 1992; Mahadevan et al., 1992), spinal and bulbar muscular atrophy (SBMA) (LaSpada et al., 1991), Huntington disease (HD) (Huntington’s Disease Research Collaborative Group, 1993), Friedreich’s ataxia (Campuzano et al., 1996), dentatrubral—pallidoluysian atrophy (DRPLA) (Koide et., 1994; Nagafuchi et al., 1994)/Haw River syndrome (Burke et al., 1994), and the spinocerebellar ataxias SCA1 (Orr et al., 1993), SCA2 (Imbert et al., 1996; Pulst et al., 1996; Sanpei et al., 1996), SCA3/Machado-Joseph disease (MJD) (Kawaguchi et al., 1994), SCA6 (Zhuchenko et al., 1997), and SCA7 (Stevanin et al., 1996).