The Effects of Genome Deletions and Frame-Shifts on Disease Severity

Muscular dystrophy is a drastic disease which causes muscle-atrophy in 1 out of every 3,500 males (O’Brien and Kunkle 2001). Those affected are commonly restrained to a wheelchair by age 12 and die in their late teens or early twenties due to complications from the disease (Davies et al. 1995). Muscular dystrophy most often appears in one of two forms; Duchenne muscular dystrophy (DMD) which is severe, or Becker muscular dystrophy (BMD) which is less severe and present later in life (Davies et al. 1995). Muscular dystrophy is caused by mutation in the gene which encodes for the protein dystrophin (Blake et al. 2002). There is no direct association between the size of the mutation within the gene, and the severity of the clinical disease (Muntoni et al. 2003). Substantial deletions, up to nearly 50% of the gene, can occur and result in BMD, the less severe form of muscular dystrophy (Blake et al. 2002). This is largely due to the central and distal rod areas of the dystrophin protein being fairly expendable (Muntoni et al. 2003). These domains can withstand large mutations and produce nothing more than myalgia and muscle cramps rather than the muscle weakness associated with the disease (Muntoni et al. 2003). Almost 65% of all muscular dystrophy patients, both with DMD and BMD, experience a dense deletion of the gene (Blake et al. 2002). While very small deletions or point mutations are most often expressed as severe DMD. It is apparent that the size of the deletion has little effect of the phenotype of the disease (Blake et al 2002). The disease’s phenotype depends little on the extent of the mutations and relies in most part on whether or not the mutation disrupts the reading frame of the gene (Blake et al. 2002). Disruption of the reading frame result in poorly constructed RNA which then produce shortened proteins in minute concentrations (Muntoni et al. 2003). In 60% of cases, dystrophin is not produced at all (Davies 1997). These mutations almost always result in a diagnosis of DMD (Davies 1997). In frame mutations, those that do not agitate the reading frame, usually result in BMD due to the gene being able to produce shorter, but still functional proteins (Muntoni et al. 2003). The connection between reading frame disruption and phenotype is true for 90% of all dystrophy cases with specific and rare