Tazswana’s Story: How Alternative mRNA Splicing Leads to Genetic Disease and Cure

News Report: (Science Newsette)

What You Thought Was “Junk” May Be as Precious as Your Own Life

by S. Catherine Silver Key

Did you know that 50% of all genetic diseases are caused by mutations in portions of genes considered “junk DNA”? That’s right, these pieces of DNA that were in the past considered unimportant are now known to be responsible for roughly half of inherited diseases including cancer, cystic fibrosis, and a blood disease called thalassemia. Why? Well, as you know, genes are made of DNA that is then transcribed into pre-messenger RNA (pre-mRNA) in the nucleus, but before the pre-mRNA leaves the nucleus to be translated into protein it has to undergo a few alterations. One of these alterations removes portions of the pre-mRNA. Much like one would remove faulty frames of a movie film and then splice the two good ends back together to make one continuous properly edited movie, pre-mRNA is also “spliced” to make the correct mRNA and the subsequent protein. What “junk” is left behind IN the nucleus is referred to as “INtrons”. The “good” portions of mRNA are “spliced” together to form mRNA and are allowed to EXIT the nucleus; they are referred to as “EXons”. The exon-containing mRNA encodes the protein-to-be. So, if the “junk” DNA that becomes “junk” mRNA (introns) does not code for the proteins that perform essential functions for the cell, how do they cause genetic disease?

To go back to the film analogy, if you do not remove the “bad” film or portion of the movie that does not add to the plot, the film length will be longer: it will be the wrong length. Leaving in a scene that really needs to be edited out may actually change or detract from the overall plot of the movie.

Alternatively, if you do cut the appropriate region of film but paste together the wrong ends, you could have a Western with an upside-down cowboy riding on his horse.

Similarly, mRNA must be spliced correctly in order to avoid mistakes in the final product. In the case of the cell, that’s a functional protein. Without the correctly sized and pasted together RNA, the resulting protein product will be defective. This is what happens roughly in half of all genetic diseases. It could be a lot worse than an upside-down cowboy: it could be fatal.

Figure 1. Pre-mRNA is cut and spliced to form mRNA. Within human cells, machinery called the splicesome (splīs-a-sōm) performs the job of scissors and tape; removing introns and splicing together exons to form mRNA.