Point mutations: small errors in the gene - Informatie voor ouders van DMD patiënten

In slightly over a quarter of all Duchenne patients (28%) a small mutation is found in the dystrophin gene. For these patients all exons are present, but a single DNA subunit (and thus of the RNA copy) is changed (figure 7). This change causes a premature stop signal and the protein translation stops too soon.

puntmutaties in DNA — Figure 1. Point mutations change only a single subunit of the DNA. As the RNA copy is based on the DNA original, this mutation is also copied into the RNA copy. In the example one of the blue subunits is altered into a red subunit. The blue subunit started a blue-yellow-yellow code, that is translated into the blue protein subunit. However, the red-yellow-yellow subunit encodes a “stop signal” (normally only present at the end of the mRNA). Due to this stop signal protein translation stops prematurely. The consequence is a non functional protein, because half the subunits are not included (half a model car does not work properly).

In addition to point mutations (one DNA subunit is replaced by another) it can also occur that one or two DNA subunits disappear or are added in an exon. This disrupts the genetic code in a similar way as when deletions and duplications happen.

Finally, small mutations can disrupt the splicing process (where introns are removed and exons are joined to form the genetic code). The start and end of all introns contain the same, specific combination of subunits, which are recognized by the splicing machinery (figure 2). If one of these specific subunits is changed, an exon will no longer be recognized, which can disrupt the genetic code (figure 3 and 4).

Ouders_012 — Figure 3. A change in a subunit of the splice site (the first two and last two subunits of an intron) abolishes the recognition of exons by the splicing machinery. In this example the yellow-green code is changed into a yellow-red code, that is not recognized by the splicing machinery. Thus the exon is not defined and not included into the mRNA (figure 4).

puntmutaties — Figure 4. The consequences of a “splice site” mutation. Due to a change in the second exon of a gene (e.g see figure 3), this exon is no longer recognized by the splicing machinery (it resembles an intron). As a result this exon is not included in the mRNA. This disrupts the genetic code (the first and third exon do not fit).