Mutation spectrum leading to an attenuated phenotype in dystrophinopathies

Abstract

Although Becker muscular dystrophy (BMD; MIM 300376) is mainly caused by gross deletions of the dystrophin gene, the nature of the mutations involved in the remaining cases is of importance because of the milder clinical course of Becker. We have extensively characterized the mRNA changes associated with five novel point mutations giving rise to a Becker phenotype, which confirm that Becker arises largely due to alterations in splicing. In two cases the milder phenotype arises because of exon skipping, leading to an in-frame deletion (c.1603-2A>C and c.4250T>A). In further two cases intronic mutations (c.4519-5C>G and c.961-5925A>C) result in complex splicing changes, but with some residual normal transcripts. The last case, c.10412T>A (p.Leu3471X), results in a truncated transcript missing only part of the COOH terminal of the protein, suggesting that this region is not crucial for dystrophin function. The detection of a low amount of dystrophin in this patient could be attributable to a reduced efficiency of nonsense-mediated decay. The results emphasize that mRNA analysis is important in defining Becker mutations and will be of value in assessing various gene therapy strategies.