A missense mutation is a specific type of DNA error where one nucleotide, a building block of DNA, is substituted for another. This alteration is significant because it results in a different amino acid being added to a protein during its construction. Imagine a recipe where one ingredient is swapped for another; the final product might be slightly different or drastically changed. Similarly, the effect of a missense mutation on a protein can range from harmless to severe.
The Role of the Genetic Code
The instructions for making every protein are stored within DNA in segments called genes. Each gene contains a sequence of nucleotides that acts as a blueprint for a specific protein. This blueprint is read in three-letter “words” known as codons.
The process begins when a gene’s DNA is copied into a messenger molecule called mRNA, which travels to the cell’s ribosome. The ribosome reads the mRNA’s codons one by one. Each codon corresponds to one of 20 different amino acids. As the ribosome moves along the mRNA, it strings together the specified amino acids in the correct order to form a polypeptide chain.
This polypeptide chain then folds into a complex three-dimensional shape to create a functional protein. The sequence of amino acids determines the protein’s final structure and function. The genetic code is the language that translates nucleotide codons into this amino acid sequence. A change in a single nucleotide can alter a codon, leading to the wrong amino acid being used, which is the basis of a missense mutation.
How Missense Mutations Affect Proteins
The consequences of a missense mutation depend on the specific amino acid substituted and its location within the protein. The impact is categorized by the chemical properties of the original and new amino acids. These outcomes range from having no noticeable effect to causing a complete loss of protein function.
In some cases, the mutation is “conservative.” This occurs when the new amino acid has similar chemical properties—such as size or electrical charge—to the one it replaced. For example, substituting one acidic amino acid for another might not significantly disrupt the protein’s structure or function. The resulting protein may work almost as well as the original, or its function might be only slightly reduced.
A “non-conservative” mutation, however, can have much more serious effects. This happens when the substituted amino acid has very different properties from the original. Replacing a small, non-polar amino acid with a large, polar one, for instance, can alter how the protein folds. This change can disrupt the protein’s shape, stability, or its ability to interact with other molecules, leading to a significant loss of function.
A single amino acid change can affect a protein’s structure at multiple levels. It can disrupt local folding patterns, like alpha-helices or beta-sheets. This disruption can prevent the polypeptide from forming its correct three-dimensional shape or stop it from joining with other proteins to form a functional complex.
Real-World Examples in Human Health
One of the most well-documented examples of a disease caused by a missense mutation is sickle cell disease. This genetic disorder results from a single nucleotide change in the HBB gene, which provides instructions for making a component of hemoglobin—the protein in red blood cells that carries oxygen. This specific point mutation causes the amino acid glutamic acid to be replaced by valine.
This single amino acid substitution alters the behavior of the hemoglobin molecule. The change from the acidic glutamic acid to the hydrophobic valine causes hemoglobin molecules to clump together, especially when oxygen levels are low. This polymerization distorts red blood cells, which are normally flexible discs, into a rigid, sickle or crescent shape. These misshapen cells can block blood flow in small vessels, leading to pain, organ damage, and anemia.
Missense mutations are implicated in many other human diseases. For example, some forms of cystic fibrosis are caused by missense mutations in the CFTR gene, which affects a protein that regulates the movement of chloride ions across cell membranes. Another example is epidermolysis bullosa, a group of skin disorders where missense mutations in genes for skin integrity proteins make the skin extremely fragile.
Comparison With Other Point Mutations
A missense mutation is one type of point mutation, or a change affecting a single nucleotide. It can be compared with other point mutations, like silent and nonsense mutations, which have different outcomes for the resulting protein.
A silent mutation is a change in a DNA codon that does not result in a different amino acid. This is possible because the genetic code is “degenerate,” meaning multiple codons can specify the same amino acid. For example, if a mutation changes the codon GTT to GTA, the cell still adds the amino acid valine. The protein’s sequence remains unchanged, so its function is unaffected.
A nonsense mutation changes a codon that specifies an amino acid into a “stop” codon. These codons signal the end of protein synthesis. This causes the ribosome to detach from the mRNA prematurely, resulting in a shortened and non-functional protein. The earlier the stop codon appears in the gene, the more truncated the protein will be and the more severe the consequences are likely to be.