Searching for the 1 in 2,400,000: A review of dystrophin gene point mutations

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Abstract
The past few years have seen a rapid increase in our knowledge of naturally occurring mutations in the dystrophin gene. Although earlier studies were limited to gross rearrangement mutations, we are now in a position to draw lessons on the molecular etiology of the remaining one‐third of cases of Duchenne and Becker muscular dystrophy (DMD, BMD) which are associated with small mutations. This paper reviews 70 published and unpublished small mutations in the dystrophin gene and asks what we can learn about their nature, their distribution, and approaches to their characterisation. Strikingly for such a well‐conserved gene, missense mutations are extremely rare, and the vast majority of DMD point mutations, like the gross rearrangements, result in premature translational termination. It seems increasingly likely that almost all cases of DMD arise solely as a result of a reduction in the level of dystrophin transcripts, and we argue that >95% of DMD mutations contribute nothing to the functional dissection of the dystrophin protein. Most of the few BMD point mutations presented here are missense mutations in the N‐terminal or C‐terminal domains or are splice‐site mutations that probably act, like BMD deletions, via the production of in‐frame, interstitially deleted transcripts.