What it means to have a mutation and what role mutations play in Huntington’s disease.
There are many safeguards against mutation. Why don’t these safeguards stop the codon expansion before it becomes harmful?
DNA interacts with many compounds that act as safeguards to repair any mutations that may occur. However, sometimes the safeguards miss the mutation, allowing it to elicit a change in the organism involved. Hundreds of millions of years ago, the safeguards missed the mutations that allowed the first animals to have lungs that could breathe air. These mutations allowed life to emerge from the sea and onto land. The safeguards also missed the mutations that allowed the first humans to stand upright, as well as the mutations that allowed people to develop the tools necessary for speech. These amazing feats would never have been achieved if the mutations would have been repaired by the safeguards. But the safeguards can also miss mutations that can have harmful results. For instance, it appears that in people with HD, the expansion mutation in the Huntington gene is not repaired by the safeguards.
One of these safeguards is called MSH2. MSH2 is what is known as a mismatch repair enzyme: it guards against bases matching up with incorrect partners (for instance, it stops adenine (A) from pairing with cytosine (C) or guanine (G)). In addition, MSH2 also repairs unpaired regions of DNA (such as bubbles resulting from polymerase slippage) and it stops hairpins from forming. Researchers believe that the problem with MSH2 in regards to HD is either that MSH2 itself becomes altered or the compounds that are essential to its effectiveness become altered. Either way, MSH2 cannot perform its normal duties and thus it cannot properly safeguard against expansion. The only problem with this model is that MSH2 only seems to be involved in stopping small-scale (usually less than 5 copies of CAG) expansion. It seems, then, that other proteins are involved in avoiding large-scale expansion. Like MSH2, if they become altered or are in some way unable to perform their normal duties, then the safeguard breaks down and expansion occurs.
Last Modified: 1-28-04
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