making muscle wasting history

Duchenne and Beckers result from variations on the dystrophin gene.
The dystrophin gene is the blueprint, or ‘recipe’ for the body to produce the protein dystrophin.

Dystrophin is a protein found in normal muscle cells which acts as a shock absorber, protecting the muscle cells. It also plays roles in cell membrane stability; it seems to have some impact on the control of the flow of certain ions. Without dystrophin muscle cells break down quickly.

The genetic information held in the dystrophin gene is made up of sections known as exons, alternating with areas called introns.
The exons are the regions which give the actual instructions to produce dystrophin. The introns between are still not completely understood, these introns are actually removed before the protein is produced during a process referred to as “splicing”.

Reading frames.

Exons along the dystrophin gene are ‘read’ in chunks of 3 bases, represented here as 3 letter words, shown in upper caes letters. The areas between (in lower case) represent the introns which, until recently, were regarded as irrelevant 'advertising junk'

THEblablablaOLDblablagobbldygookFATrubbishstuffMANnonsensestuffANDblablablaHISblablablaOLDblablablaFATblabla
blaDOGblablablaRANblablablaANDblablablablaRANblablablablaANDblablablablaRANblablablaANDblablablablaRANblabla
blaFORblablabladdyblaTHEblablaBUSblablablaEND

This is copied to pre-messenger RNA:
This copy is then spliced (the introns removed and the exons spliced back together) to form the new copy called messenger RNA:

THEOLDFATMANANDHISOLDFATDOGRANANDRANANDRANANDRANFORTHEBUSEND

This may look odd but if we add spaces to show how the 3 letter words will actually be read it makes sense:

THE OLD FAT MAN AND HIS OLD FAT DOG RAN AND RAN AND RAN AND RAN FOR THE BUS END

‘END’ represents the stop codon, which is the signal at the end of the code indicating to the ribosomes (area of the cell which produces the protein) that the protein is complete, and so at that point the protein production ceases.

Some genetic variations resulting in Duchenne are due to what is known as a premature stop codon, where this “END” signal appears in a region of the code before it should. The code is only read up until this “END” signal and protein production halts before the dystrophin has actually been formed. Such genetic variations are relevant for the PTC124 drug which is on trial in the UK currently. This drug enables a premature stop codon to be ignored.

The majority of cases (60%) of Duchenne are due to deletions of entire exons, where whole exons are missing.
We can demonstrate how deletions have an effect of the ‘reading frame’ , in the following example the first ‘F' and ‘A’ are deleted (for ease the gaps are shown as XX )
THE OLD XXT MAN AND HIS OLD FAT DOG RAN AND RAN AND RAN AND RAN FOR THE BUS END
The code is still read in chunks of 3 and this is where problems occur, no allowance is made for the fact that some letters are missing:

THE OLD TMA NAN DHI SOL DFA TDO GRA NAN DRA NAN DRA NAN DRA NFO RTH EBU SEN D

The message left by this deletion does not make sense and cannot be read, which results in production of the protein coming to a halt. This is what is referred to as an out of frame deletion.

Such deletions result in disruption of the reading frame.

How exon skipping restores the reading frame

Exon skipping aims to put the message back in frame, leaving a message which can be read. In the same example, if we ‘patch’ one more letter, hiding it, we will be left with a message which can make sense:
THE OLD XX~ MAN AND HIS OLD FAT DOG RAN AND RAN AND RAN AND RAN FOR THE BUS END

XX= original missing exons, ~ = exon hidden by the genetic patch (oligonucleotide)

This now leaves the message reading:

THE OLD MAN AND HIS OLD FAT DOG RAN AND RAN AND RAN AND RAN FOR THE BUS END

The reading frame is restored, the whole remaining message can be read, although it does have a part missing. This is how exon skipping works, it takes an out of frame code error, hides part of the code on the RNA copy, to put the code back in frame. This is effectively turning a Duchenne mutation into a Beckers one, and from this patched code a shortened but functional dystrophin protein can be made in most cases.

As general rule (in 99% of cases tested at RNA level), if a deletion at RNA level is out of frame, this results in no dystrophin production, and hence a diagnosis of Duchenne.
If a deletion at RNA level is in frame (ie a piece of information is missing but the code can still be read and make sense) then a shortened form of dystrophin is produced, and hence a diagnosis of Beckers is appropriate.

The severity of Beckers varies greatly, much of this variation is probably due to where the deletion occurs within the chain of exons, and how large that deletion is. Larger deletions of exons (those with around 35 exons missing) or deletions at certain locations within the exon chain may result in lack of dystrophin production, even if the remaining code is in frame. But such cases are relatively rare and other potential treatments are looking very hopeful for these, and other variations for which exon skipping will not be a viable option.

Further information on exon skipping here:
Exon Skipping