Gene mutations are changes in the DNA sequence. These alterations can range from minor changes to large-scale rearrangements, and while some have no noticeable effect, others significantly impact an organism’s traits or health. This article explores frameshift mutations, examining their mechanism and consequences.
Understanding the Genetic Code
The genetic information within DNA is organized into genes, which contain instructions for building proteins. Proteins perform most cellular work and are essential for the body’s structure, function, and regulation.
To create a protein, the cell “reads” the DNA sequence precisely. This process relies on the genetic code, where information is encoded in triplets of DNA bases, known as codons. Each codon specifies a particular amino acid, the building blocks of proteins, or signals the start or end of a protein sequence.
Cells read these codons sequentially and without overlap, establishing a specific “reading frame” that determines the correct order of amino acids in a protein. For instance, if a sequence of letters were “THE BIG DOG,” the cell reads “THE,” then “BIG,” then “DOG,” interpreting each three-letter word as a distinct instruction.
What is a Frameshift Mutation?
A frameshift mutation occurs when there is an insertion or deletion of nucleotides in a DNA sequence, and the number of inserted or deleted nucleotides is not a multiple of three. This type of mutation disrupts the established reading frame of the genetic code.
Imagine the sentence analogy “THE BIG DOG ATE THE FAT RAT.” If a single letter, like ‘A’ from “ATE,” is deleted, the sentence becomes “THE BIG DOG TET HEF ATR AT.”
Because the cell reads in groups of three, the removal or addition of one or two nucleotides fundamentally alters how all subsequent codons are grouped and interpreted. Every codon downstream from the mutation point will be misread, whether due to insertion or deletion.
Impact on Protein Synthesis
The consequences of a frameshift mutation on protein synthesis are severe. Since the reading frame is altered, the cell assembles a completely different sequence of amino acids from the point of the mutation onward.
One common outcome is the premature appearance of a “stop” codon within the shifted reading frame. When this happens, protein synthesis terminates much earlier than intended, resulting in a truncated, or abnormally shortened, protein.
These shortened proteins are usually non-functional or have severely impaired function because they lack regions necessary for their proper three-dimensional structure and activity. Even if a premature stop codon is not introduced, the altered sequence of amino acids can drastically change the protein’s shape, rendering it unable to perform its specific cellular role.
Diseases Caused by Frameshift Mutations
Frameshift mutations are underlying causes for a number of genetic disorders. These mutations disrupt the production of functional proteins, leading to a variety of health conditions. Examples include Tay-Sachs disease and certain forms of Crohn’s disease.
Tay-Sachs disease, a severe neurological disorder, is caused by frameshift mutations in the HEXA gene. These mutations lead to a non-functional beta-hexosaminidase A enzyme, which is essential for breaking down a fatty substance called GM2 ganglioside. The accumulation of this substance in brain cells results in progressive damage and the characteristic symptoms of the disease.
Similarly, some cases of Crohn’s disease, an inflammatory bowel condition, are associated with a frameshift mutation in the NOD2 gene, specifically a cytosine insertion at position 3020. This insertion causes a premature stop codon, leading to a shortened and non-responsive NOD2 protein that cannot properly regulate the immune response to bacteria in the gut.