Muscular dystrophies are inherited degenerative disorders affecting skeletal muscles leading to progressive weakness. The commonest adult muscular dystrophy is myotonic dystrophy type 1 (DM1) (OMIM 160900) with a prevalence of about one in 8000 people (Machuca-Tzili et al. 2005). Myotonic dystrophy is a specific type of muscular dystrophy in which myotonia is seen: abnormal electrical activity is found at muscle fibre membranes, manifest clinically with difficulty relaxing the grip, and also affecting talking, chewing, and swallowing.
The other distinct feature of myotonic dystrophies is the multisystem involvement that is manifest, involving brain (for example cognitive impairment, daytime sleepiness, psychological and personality traits), eyes (cataracts), heart (cardiac conduction abnormalities), and endocrine (insulin resistance, testicular atrophy) systems. For DM1, clinical anticipation is recognized with severely affected children born to mothers with minimal symptoms (Koch et al. 1991). Congenital, childhood, and adult onset forms of DM1 are recognized.
The (CTG)n and (CCTG)n repeat expansions found in the 3' UTR of the DMPK gene, and intron 1 of ZNF9, results in RNA with long CUG and CCUG tracts, respectively. RNA was shown to be retained in the nucleus in DM1 (Davis et al. 1997). Moreover, the presence of CUG repeats in a transcript was sufficient to cause disease. In a transgenic mouse when a (CTG) expansion was inserted into the 3' UTR of an unrelated gene, human skeletal actin, features of myotonia were seen (Mankodi et al. 2000). The myotonic dystrophy phenotype was also seen with transgenic mice producing DMPK RNA with at least 300 CUG repeats (Seznec et al. 2001).
Misregulation of alternative splicing for specific genes is found to occur in patients with myotonic dystrophy resulting in the presence of specific alternatively spliced isoforms, involving for example the muscle-specific chloride channel (CLCN1), insulin receptor (IR), and cardiac troponin T (cTNT) (Savkur et al. 2001; Charlet et al. 2002; Mankodi et al. 2002). The presence of particular isoforms has important consequences, for example reduced chloride channel expression and defective insulin signalling in skeletal muscle results in specific disease manifestations such as myotonia and insulin resistance. The basis for this effect on splicing was found to relate to the interaction of specific RNA binding proteins with the repeat expansions found in the DMPK and ZNF9 RNA molecules. Musclebind-like (MBNL) protein and CUG binding protein (CUG-BP1) can bind CUG repeats and modulate splicing; the former interaction being dependent on repeat length (Timchenko et al. 1996; Philips et al. 1998; Miller et al. 2000). The result is loss of function for MBNL and gain of function for CUG-BP1, altering RNA splicing with a diverse range of consequences depending on the specific proteins whose splicing is modulated (Fig. 7.11). A knock-out mouse model for MBNL leads to characteristic features of myotonic dystrophy (Kanadia et al. 2003) while overexpression of CUG-BP1 in skeletal and heart muscle (Ho et al. 2005b) reproduced features of the disease.
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