Genetic diseases are familiar to all of us, even if we or a close friend/relative are not directly affected. They are diseases which can be passed on from generation to generation and can affect people for their whole lives. Defects in splicing are responsible for 15-50% of the genetic diseases out there. In this last post on splicing, I want to highlight how such defects can lead to disease using two examples.
Individuals with this syndrome exhibit problems in sex determination and kidney development. They also carry an increased risk of developing tumours in genitourinary regions.
Now if you remember from previous posts, I talked about how alternative splicing can allow different exons to be incorporated or excluded in the final mRNA. This can lead to the production of proteins that have different functions. In a healthy individual without the disease, this is exactly what happens. A particular gene leads to the production of 2 proteins of distinct function. One protein is involved in assisting the production of mRNA from other genes. The other is involved in regulating alternative splicing (we’ll come back to this in a minute). The ratio of these 2 proteins is very important in guiding correct sex determination and kidney development.
In individuals with Frasier syndrome, what happens is that there is a mutation that prevents exons from being included or excluded correctly. Alternative splicing therefore isn’t happening in the appropriate way. The 2 proteins are still made but they are not made in the right quantities. The ratio of the proteins is skewed. If you’re not a scientist, imagine this being a bit like baking cookies. You might need to add both sugar and salt but if you don’t add them in the correct amounts and their ratio is skewed, you’ll either get cookies which are too salty or sickeningly sweet.
So, not only is alternative splicing not happening correctly, one of the proteins which is involved in regulating alternative splicing is being produced at incorrect levels. This protein will affect the splicing of other mRNAs and the correct formation of other proteins.
Individuals with Myotonic Dystrophy (MD) have severe muscle weakness, due to this being a progressive muscle wasting disease, and insulin resistance.
In individuals with MD, a repeat expansion mutation in the DNA causes an abnormal mRNA to be produced. This abnormal mRNA has two effects. Firstly, it sequesters a protein known as MBNL in the nucleus. This means it anchors many copies of this protein and prevents them from doing their normal job which is to regulate splicing. Secondly, it stimulates a protein known as CELF to higher than normal levels. CELF is also involved in regulating splicing.
During regular development, MBNL activity increases and CELF activity decreases - this is the case in individuals without MD. However, those who do have MD have this balance or ratio disrupted because of the anchoring and stimulating I just described. This disruption in the balance of these proteins that regulate alternative splicing leads to proteins such as the insulin receptor not being produced properly.
What I hope to have done, with these three posts on splicing, is illustrate the importance of splicing. Scientists all over the world are working to understand alternative splicing - how it is regulated, where and by what. Not only because it poses interesting intellectual questions but also because defects in splicing affect many people with genetic diseases and this could potentially be a point of therapeutic intervention in the future.