The human genome is the body’s instruction manual, written in a four-letter alphabet. Sometimes, single-letter typos, known as genetic variants, occur in this genetic text. A missense variant is a common type of these alterations and represents a specific kind of change in the DNA code.
From DNA Code to Protein Building Block
Genes are individual recipes within the DNA that hold instructions for making proteins. Proteins are complex molecules that perform tasks like carrying oxygen in the blood and digesting food. The process of turning a gene into a protein involves two steps: transcription and translation.
The process begins in the cell’s nucleus, where the DNA recipe is transcribed into a molecule called messenger RNA (mRNA). This mRNA acts as a temporary message, carrying the instructions out of the nucleus and into the cytoplasm. Once in the cytoplasm, a molecular machine called a ribosome reads the instructions to build the protein.
The ribosome reads the mRNA’s genetic code in three-letter “words” known as codons. Each codon corresponds to a specific amino acid, the building blocks of proteins. Transfer RNA (tRNA) fetches the correct amino acid for each codon and adds it to a growing chain. This process, called translation, continues until the ribosome reaches a “stop” codon, signaling the protein is complete.
Defining a Missense Variant
A missense variant is a point mutation, a change in a single DNA nucleotide, or one letter of the genetic code. This single-letter alteration is significant because it changes a codon, causing the cell’s machinery to read a different instruction. The result is the substitution of one amino acid for another during protein assembly.
Using a cookbook analogy, if an instruction reads “ADD FLOUR,” a missense variant is like a typo changing “ADD” to “LAD.” The instruction is still a readable, three-letter word, but it now calls for a different ingredient. This change alters the composition of the final product.
In contrast, a “silent” variant is a typo that doesn’t change the final protein because the new codon still codes for the same amino acid. A “nonsense” variant changes a codon for an amino acid into a “stop” codon. This change prematurely halts protein construction, resulting in a shortened, nonfunctional protein.
The Spectrum of Impact on Health
The health consequences of a missense variant exist on a wide spectrum, from harmless to the cause of a severe condition. The effect depends on the nature of the amino acid substitution and its location within the protein. If the new amino acid has chemical properties similar to the original, or if the change is in a less important region, the impact may be negligible.
If the substituted amino acid is chemically different, it can alter the protein’s three-dimensional shape. A protein’s shape is tied to its function, so a misfolded protein may not work correctly. The location is also important, as a change in a protein’s active site is more likely to have a significant effect than a change on its surface.
To manage this uncertainty, clinical geneticists classify variants into five categories: Pathogenic, Likely Pathogenic, Benign, Likely Benign, and Variant of Uncertain Significance (VUS). Pathogenic variants cause disease, while benign variants are harmless. A VUS classification means there is not enough data to place the variant in either category. This is a statement of uncertainty, not a diagnosis, and may be reclassified as more research becomes available.
Real-World Examples of Missense Variants
Sickle cell disease is a clear example of a missense variant’s impact. The condition is caused by a point mutation in the HBB gene, which provides instructions for making hemoglobin, the protein in red blood cells that carries oxygen. This variant changes the codon for the sixth amino acid from GAG to GTG, resulting in the substitution of glutamic acid with valine.
This single amino acid swap alters the chemical properties of the hemoglobin molecule, causing the proteins to clump together when oxygen levels are low. These clumps distort red blood cells from their flexible disc shape into a rigid, sickle-like crescent. These misshapen cells can block blood flow and break apart easily, leading to the severe symptoms associated with the disease.
Cystic fibrosis is another condition linked to missense variants. The disease is caused by mutations in the CFTR gene, which codes for a protein that regulates chloride ion flow across cell membranes. While its most common mutation is a deletion, many missense variants also cause the disease by impairing the CFTR protein’s ability to fold or function correctly.