What are Genetic Mutations?

What is DNA?

Our DNA is the foundational instruction manual that our bodies use to create everything: from our fingernails to our beating hearts. But how does DNA, a molecule not visible to the eye, have so much control over how our bodies are built and function?

Do you remember alphabet soup? Picture those small noodle letters are set down in a row, and that the row stretches six feet long. Now, imagine an ant moving along this row to read each individual letter in order to know what to build. It would be quite the undertaking for the ant!

Similarly, the DNA found in each of our cells is expansive, and every part of it needs to be ‘read’ in order to make our bodies into what they are. Luckily for us, DNA is more user-friendly than an ant reading six feet of alphabet noodles; our DNA is divided into individual subsections known as genes. Each gene plays a role in providing our bodies with unique information on how to build our individual forms.

In order for the information in our DNA to be used, genes must first be converted to RNA. Each gene can be individually converted to RNA. This means that genes only become RNA when they need to, saving the cell crucial energy. What exactly does RNA do? RNA serves as the intermediate step between genes and proteins. These proteins then go on to perform a variety of functions that make our bodies what they are.

Figure 1. DNA is converted into RNA, which is used to make the final product our bodies use, proteins.

What is a mutation?

As we mentioned, our DNA is the instruction manual that our bodies use throughout the course of our lives. However, sometimes the instructions get altered. Errors in our DNA are known as mutations, and these mutations ultimately result in our bodies being given different sets of instructions. Mutations occur when a letter in our DNA instructions, also known as a nucleotide, is changed. In some instances, mutations have no effect on our bodies and how they function. However, some mutations have severe consequences. How do different mutations result in such drastically different outcomes?

These different outcomes are partly dependent on what type of mutation occurred in the gene. A brief overview of the different types of mutations is presented below:

• Missense mutation: A single nucleotide in the DNA is changed to a different letter.
• Nonsense mutation: Similar to a missense mutation, a nonsense mutation occurs when a nucleotide is changed to a different letter. However, these specific mutations instruct for a premature stop to reading the DNA.
• Repeat expansion mutation: The same segment of DNA is repeated multiple times.
• Frameshift mutation: Disrupts the order in which the nucleotides occur, thus ‘shifting’ how the DNA is read.
  • Insertion mutation: Adds an extra nucleotide
  • Deletion mutation: Removes a nucleotide
• Silent mutation: Nucleotide change does not affect the ultimate result (protein).

Figure 2. Examples of different types of mutations described in the bulleted list above. Using the DNA in the upper left corner as your reference, follow the highlighted areas and arrows to see how each type of mutation affects the DNA.

How do mutations affect proteins?

If the instructions we have on how to build a dresser are mistyped, we won’t be able to correctly assemble that dresser, right? The same rule applies for mutations. If a mutation alters how a gene is read, the protein that comes from that gene will also be affected. A single protein has many jobs to do, all of which ultimately boil down to the protein performing the correct function, at the right place, at the right time. Depending on what the mutation is, one or all of these protein jobs can be disrupted.

Brief examples of what mutations can do to protein function:

• Change the location of a protein in a cell
• The protein no longer performs efficiently, or at all
• No protein is made in the cell

Figure 3. Cells need to localize different proteins to different regions of the cell in order to form correct structures. When the pink proteins are not localized correctly to the end of the long cell extension, the extension is cut short (indicated by the arrow), which affects the cell’s function.

SLC13A5 gene mutations

Mutations that alter an important factor of protein function can ultimately have large-scale adverse effects on our bodies. In the case of mutations in the SLC13A5 gene, these mutations alter the function of the sodium (Na) dependent citrate transporter protein (or NaCT, for short). The NaCT protein is located at the edge of the cell and is necessary for transporting citrate (a crucial molecule for making energy) into cells.

When there is not enough citrate brought into cells in the brain, energy levels become depleted, and seizures and neurological disorders arise. While we still do not fully understand how decreased citrate transport is connected to seizures and neurological problems, scientists and physicians are filling in the missing puzzle pieces by studying the different mutations found in the SLC13A5 gene.

There are over 40 different mutations found in the SLC13A5 gene, and they all result in ineffective or completely non-functional NaCT. Because these mutations are located in different parts of the gene, the effects they have on the protein are also varied.

The most common SLC13A5 mutation seen in patients is a missense mutation and has these defining characteristics:

• Change in DNA: This mutation occurs at the 655^th nucleotide of the SLC13A5 gene.
• Localization in cell: There is low abundance of NaCT at the edge of the cell.
• Changes in function: NaCT has decreased activity and brings less citrate into cells.

Scientists and physicians are using information like this to better understand and develop treatment options, with the goal of making the mutated NaCT proteins better at their jobs. Learning about all of these genes and mutations takes a lot of time, and we are continuing to discover more about how SLC13A5 works.

Thank you to Katie Hoff, a Molecular Biology graduate student at the University of Colorado Anschutz Medical Campus for writing this article!