Multiple exon skipping and RNA circularisation contribute to the severe phenotypic expression of exon 5 dystrophin deletion

Abstract

Deletion and duplication of one or more exons in the dystrophin gene account for 70% of patients with Duchenne and Becker muscular dystrophies (DMD and BMD) and other allelic clinical entities such as raised serum creatine kinase and X linked dilated cardiomyopathy (XLDC).1 The severity of the resulting phenotype can be generally predicted by whether these mutations lead to translation frame disruption and premature termination of protein synthesis.2 Nevertheless, the occurrence of severely affected patients with in frame deletions as well as mild phenotypes associated with frameshift, indicate that factors other than the frame disruption should contribute to the clinical severity. Exceptions to the “frame rule” are found in about 8% of patients with mutations occurring both at the 5′ and 3′ end of the dystrophin gene,1,3,4 although they seem to predominate in the 5′ region.4 Despite extensive clinical, immunocytochemical, and transcriptional studies, the basis of genotype-phenotype correlation in these “atypical” cases remains controversial and its clarification will surely provide relevant information about normal and abnormal dystrophin function. Several reports suggest a role for alternative splicing in altering the clinical phenotype by modulating the editing of the translation reading frame.3,5,6 Patients with BMD carrying the frameshift deletions of exons 3–7 and 45 show alternative splicing phenomena theoretically restoring the reading frame.5,7 However, the relevance of these events in contributing to a milder phenotype is still unclear.3,8,9 Supporting the bridging role of the dystrophin splicing machinery as active modulator between genotype (deletion mutation) and protein production, cell specific somatic exon skipping has been documented in skeletal muscle revertant fibres in DMD.10 ### Key points