Week 6: Teenage Mutant Ninja TYRtles

What Are Mutations?

At last! The main cause of OCA1 will finally be discussed (dun dun duun). Mutations are changes in the DNA sequence. Everybody makes mistakes, including RNA polymerase. As a refresher, RNA polymerase is the enzyme responsible for making the mRNA pre-transcript in the transcription process. Like some college students who frantically submit their English essays at 11:58 PM (🙋🏻‍♀️), RNA polymerase does not proofread its work on the DNA strands. It assumes that if it makes A LOT of correct transcripts, then it can make up for its one bad transcript. This overconfidence, ladies and gentlemen, is only one of many factors that can explain why mutations arise. Changes in the DNA sequence can also be environmentally influenced and/or come about during the DNA replication process. 

Translation Overview

Before we dive deeper into mutations, we need to understand a bit about translation. As mentioned in an earlier blog post, while transcription’s goal is to make RNA, translation’s goal is to make protein. To put into our context, the TYR gene in the DNA goes through transcription to be converted into mRNA. Then, the mRNA is translated from RNA language to protein language to make our tyrosinases. 

Translation takes place on ribosomes in the cell cytoplasm. It requires the help of rRNA (ribosomal RNA) found in the ribosome structure, tRNA (transfer RNA), microRNA, and other proteins. Each group of three nucleotides in the mRNA sequence, called a codon, unambiguously codes for a certain amino acid. There is redundancy because many codons can code for the same amino acid. Our 20 amino acids are universal, meaning that they are the same for eukaryotes and prokaryotes. 

The start codon (AUG) signals our ribosome to begin translating the mRNA and combining the amino acids into a long, polypeptide chain. The stop codon (either UAA, UGA, and UAG a.k.a. U Are Annoying, U Go Away, and U Are Gone) signals everything to disassemble so that we are left with our pre-folded protein!

Now that we are wiser beings, let’s look at the different types of mutations.

Types of Mutations

1. 1. A point mutation changes a single DNA base pair
   2. A silent mutation DOES NOT change the amino acid that it codes for
   3. A missense mutation DOES change the amino acid that it codes for
   4. A nonsense mutation codes for a stop codon
   5. An insertion or deletion (indel) adds or removes a DNA base pair to shift the reading frame and consequently change all of the amino acids being coded

As you can hopefully see, some mutations are not as harmful as others. For example, a silent mutation compared to an indel mutation differs a lot in severity. One does not change the amino acids at all while the other changes all of them. This demonstrates that mutations are simply changes in the DNA sequence and should not be generalized as destructionists.

Mutations in the TYR gene

In 2016, there were about 350 mutations detected in the TYR gene. 77% of the mutations were missense, 15% were deletions, and 3% were insertions (1). All of these mutations change the amino acids that are coded and therefore can change the final tyrosinase structures. The mutations would determine what type of OCA1, A or B, one would have. If they destroy tyrosinase activity entirely, then they lead to OCA1A, where there is more permanent oculocutaneous albinism. If they allow some of the tyrosinases to stabilize (1) and function –which means that more melanin can be made with age – then they lead to OCA1B (3). 

Some of the mutants responsible for deletions in OCA1A are named M370T, N371Y, P313R, T373K (2); another mutant is R77Q. As for mutants in OCA1B, there are P406L, R402Q, R422Q, and R422W (1). 

References

1. Dolinska, M. B., Kus, N. J., Farney, S. K., Wingfield, P. T., Brooks, B. P., & Sergeev, Y. V. (2017). Oculocutaneous albinism type 1: Link between mutations, tyrosinase conformational stability, and enzymatic activity. Pigment Cell & Melanoma Research, 30(1), 41–52. https://doi.org/10.1111/pcmr.12546
2. K, B., & Purohit, R. (2013). Mutational analysis of Tyr Gene and its structural consequences in OCA1A. Gene, 513(1), 184–195. https://doi.org/10.1016/j.gene.2012.09.128
3. Kamaraj, B., & Purohit, R. (2014). Mutational analysis of oculocutaneous albinism: A compact review. BioMed Research International, 2014, 1–10. https://doi.org/10.1155/2014/905472