Long mutant dystrophins and variable phenotypes: evasion of nonsense-mediated decay?

Abstract.

More than 98% of Duchenne muscular dystrophy (DMD) mutations result in the premature termination of the dystrophin open reading frame at various points over its 11-kb length. Despite this wide variation in coding potential (0%–98.6% of the full-length protein), the truncating mutations are associated with a surprisingly uniform severity of phenotype. This uniformity is probably attributable to ablation of the message by nonsense-mediated decay (NMD). The rare truncating mutations that occur near the 3' end of the dystrophin gene (beyond exon 70) can however result in extremely variable phenotypes (both intra- and inter-familially). We suggest that all proteins encoded by such mutant genes are capable in principle of rescuing the DMD phenotype but that NMD abrogates the opportunity to effect this rescue. The observed variability may therefore reflect an underlying variation in the efficiency of NMD between individuals. We discuss this hypothesis with particular reference to a well-characterised Becker muscular dystrophy patient with a frameshift mutation, where expression of a truncated dystrophin rescues the muscular but not mental phenotype.