Applicability

Exon skipping for DMD mutations

The majority of patients (~70%) has a deletion of one or more exons, while duplications are found in ~7% and small mutations in almost 25% of patients. Exon skipping has been confirmed to restore the open reading frame of patients with deletions, point mutations and small duplications. Tables indicating which exon(s) needs to be skipped to restore the reading frame for common deletionsduplications and point mutations can be accessed. Please note that these tables are based on a 2004 version of the Leiden DMD mutation database and that new mutations have been added since. If a certain mutation is not present in the tables, exon skipping could still be possible.

You can send us your mutation and we will be able to determine whether exon skipping is theoretically feasible and if so which exon(s) needs to be skipped. More information about exon skipping for deletionsduplications and point mutations can be found on our website.


Mutation specificity and applicability

The exon skipping approach is mutation specific, i.e. for different mutations. The skipping of different exons is required to restore the open reading frame. However, deletions and duplications do not occur random throughout the DMD gene, but are located in deletion hotspots. Of all deletions, 70% is located between exon 45 and exon 55 (major deletion hotspot), while 23% lies between exon 2 and exon 20 (minor deletion hotspot). Therefore, the skipping of some exons can restore the reading frame for different deletions, e.g. skipping exon 51 is  theoretically therapeutic for the following deletions: exon 13-50,  29-50, 43-50, 45-50, 47-50, 48-50, 49-50 and 52, which totals on 25% of all deletions (or 16% of all mutations). By choosing exons strategically, skipping of only 10 different exons can be therapeutic for over 50% of patients in the Leiden DMD mutation database. These exons are: 2, 8, 43, 44, 45, 46, 50, 51, 52 and 53.

There are some mutations for which exon skipping is not applicable. These include deletions containing the first or the last exon, mutations involving exon 64-70 (which code for the essential cysteine-rich domain), large deletions that involve both the actin-binding domain and a major part of the central rod domain and large rearrangements such as inversions and translocations. However, these mutations are rare and together make up less than 10% of all mutations seen in patients.