Revertant Fibres

Revertant fibres are dystrophin-positive fibres that have been detected immunohistochemically in dystrophic muscle. These dystrophin-positive fibres are found in most animal models of muscular dystrophy, and at least 50% of DMD patients (Hoffman et al. 1990; Klein et al. 1992; Schatzberg et al. 1998; Sherratt et al. 1993; Wallgren-Pettersson et al. 1993; Wilton et al. 1997). The dystrophin in revertant fibres has been shown to be internally deleted, with RNA and protein studies involving epitope mapping indicating that many exons have been omitted from the mature mRNA (Klein et al. 1992; Lu et al. 2000; Sherratt et al. 1993; Wallgren-Pettersson et al. 1993; Wilton et al. 1997). The natural exon skipping by-passed either a nonsense mutation or a frame-shifting re-arrangement and resulted in a transcript that could be translated into a Becker-muscular-dystrophy-type protein. It should be noted that the revertant fibres in the animal models or the human cases are not uniform, but rather represent a variety of exonic combinations (Lu et al. 2000; Wallgren-Pettersson et al. 1993; Wilton et al. 1997).

The incidence of revertant fibres is too low to be of any clinical benefit (Fanin et al. 1995) but these dystrophin-positive fibres demonstrate that some natural, albeit low level, exon skipping mechanism can by-pass mutations that would have otherwise induced the premature truncation of dystrophin synthesis. The origin of dystrophin in revertant fibres is not known but could be due to either a secondary genomic deletion to remove the primary gene lesion and restore the reading frame, or some alternative splicing mechanism allowing multiple exons to be skipped from the mature dystrophin transcript. Genomic deletions are common in the dystrophin gene and provide some indirect evidence for a somatic mutation origin for revertant fibres. However, in situ hybridization studies using an mdx mouse intron 23 genomic probe indicated that there were no genomic deletions in the majority of dystrophin-positive fibres, suggesting some alternative processing of the dystrophin pre-mRNA (Lu et al. 2000). Regardless of their origin, an important feature of revertant fibres is that exon skipping in the dystrophin gene does occur naturally, and since these dystrophin-positive fibres persist, the dystrophin is at least partially functional, and the immune system should be tolerant to some dystrophin.

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