Duchenne Muscular Dystrophy and Brain Function

Muscular dystrophies have historically been characterised according to clinical criteria, however in the genomic age the muscular dystrophies are now subdivided into groups according to the primary gene defect. Currently identified are 29 different loci and encoded proteins, giving rise to 34 distinct forms of muscular dystrophy (Dalkilic & Kunkel 2003; Hsu 2004). The majority of these types of muscular dystrophy are caused by perturbations of different components of the dystrophin-glycoprotein complex (DGC) an integral component of the cellular cytoskeleton (see below). Dystrophin is the largest component of the DGC and is absent in Duchenne muscular dystrophy (DMD), and severely truncated with decreased levels in Becker muscular dystrophy (BMD) (Hoffman & Kunkel 1989). DMD and the allelic BMD are the most common forms of muscular dystrophy in humans and together they are termed dystrophinopathies (Kingston et al. 1984; Shaw & Dreifuss 1969). DMD alone accounts for approximately 80% of all the myopathies in the muscular dystrophy group (Culligan et al. 1998).The dystrophin gene is the second largest described to date, totalling 1.5% of the X chromosome, 0.1% of the entire genome. The DMD gene is 99% introns, with a coding sequence of 86 exons (including the promoters) and remains the only known human metagene (Blake et al. 2002; Burmeister et al. 1988; Hamed & Hoffmann 2006; Kenwrick et al. 1987; Koenig et al. 1987; Kunkel et al. 1986; Muntoni et al. 2003; Roberts et al. 1993; Smith et al. 2006; Van Ommen et al. 1987; Wallis et al. 2004). Dystrophin was demonstrated to be localised at the sarcolemma in human skeletal muscle after its’ genetic characterisation (Arahata et al. 1988; Sugita et al. 1988; Zubrzycka-Gaarn et al. 1988). This discovery was followed by a report of dystrophin messenger RNA in brain, with the protein being specifically localised at postsynaptic densities (PSD) in the CNS, in particular in the hippocampus, cerebral cortex and in cerebellar Purkinje cells (PC) (Chamberlain et al. 1988; Chelly et al. 1988, 1989; Lidov et al. 1990, Nudel et al. 1988).