SPECTRUM OF SMALL MUTATIONS IN THE DYSTROPHIN CODING REGION

Duchenne and Becker muscular dystrophies (DMD and BMD) are caused by d efects in the dystrophin gene. About two-thirds of the affected patien ts have large deletions or duplications, which occur in the 5' and cen tral portion of the gene. The nondeletion/duplication cases are most l ikely the result of smaller mutations that cannot be identified by cur rent diagnostic screening strategies. We screened similar to 80% of th e dystrophin coding sequence for small mutations in 158 patients witho ut deletions or duplications and identified 23 mutations. The study in dicates that many of the DMD and the majority of the BMD small mutatio ns lie in noncoding regions of the gene. All of the mutations identifi ed were unique to single patients, and most of the mutations resulted in protein truncation. We did not find a clustering of small mutations similar to the deletion distribution but found >40% of the small muta tions 3' of exon 55. The extent of protein truncation caused by the 3' mutations did not determine the phenotype, since even the exon 76 non sense mutation resulted in the severe DMD phenotype. Our study confirm s that the dystrophin gene is subject to a high rate of mutation in Cp G sequences. As a consequence of not finding any hotspots or prevalent small mutations, we conclude that it is presently not possible to per form direct carrier and prenatal diagnostics for many families without deletions or duplications.