Missense Mutation: Definition, Causes, Mechanism, Types, Applications, and Example

Table of Contents

• Introduction to Missense-Mutation
• Causes of the missense mutation
• Mechanism of missense mutation
• Types of Missense Mutation
• Applications of missense mutation
• Examples of missense mutation
• References

Introduction to Missense-Mutation

• A missense mutation refers to a genetic mutation in which a change in a single nucleotide base within a gene sequence leads to the incorporation of a different amino acid during protein synthesis.
• It is classified as a type of nonsynonymous substitution in the DNA sequence, meaning the mutation alters the resulting amino acid sequence of the protein.
• The impact of a missense mutation is influenced by the specific location of the altered nucleotide and the nature of the substitution.
• In some instances, the nucleotide change may occur at a position that does not significantly impact the messenger RNA (mRNA) or the resulting protein.
• Because multiple codons can code for the same amino acid, there are situations where the altered codon still translates into the original amino acid; in such cases, the mutation is considered a silent mutation.
• However, in other cases, the substitution can be more detrimental, potentially disrupting the protein’s structure or function.
• Severe missense mutations can lead to the complete loss of protein function, which may result in various human genetic disorders.
• Examples of diseases caused by harmful missense mutations include sickle cell anemia, amyotrophic lateral sclerosis (ALS), and epidermolysis bullosa.

Causes of the missense mutation

• Missense mutations, like many other types of genetic mutations, can arise either spontaneously or through the action of external mutagens.
• These mutations frequently occur during DNA replication, where a point mutation takes place at a specific location within the DNA sequence.
• Spontaneous mutations are commonly observed during processes such as DNA replication and DNA processing.
• These spontaneous changes may involve a single nucleotide (point mutation) or span a broader region of the sequence, resulting in a frameshift mutation.
• Induced mutations, on the other hand, are often triggered by various physical agents such as X-rays and ultraviolet (UV) radiation.
• Such radiation can cause ionization of cellular molecules, ultimately altering the chemical structure of the DNA molecule.
• In addition to physical agents, certain chemical substances like reactive oxygen species (ROS), which are generated during normal biochemical reactions within the body, can act as mutagens and contribute to mutation development.
• Induced mutations typically affect the structure of the double-stranded DNA helix, while spontaneous mutations can occur in either a single strand or both strands of DNA.
• During DNA replication, nucleases may also degrade portions of the sequence, thereby altering the original genetic code and contributing to mutation formation.

Mechanism of missense mutation

• The mechanism behind a missense mutation varies depending on the underlying cause of the mutation.
• Common mechanisms that lead to missense mutations include nucleotide deletion, substitution, insertion, and transformation.
• One of the most frequent mechanisms is a tautomeric shift in nucleotides, where the movement of hydrogen atoms alters the base’s bonding properties.
• Each nucleotide base can exist in two tautomeric forms: the keto form (common) and the enol form (rare).
• A shift from the keto to the enol form can disrupt normal complementary base pairing during DNA replication.
• This mispairing affects the mRNA sequence transcribed from the DNA and ultimately leads to changes in the amino acid sequence of the translated protein.
• In some cases, deletion of a specific nucleotide from the DNA sequence results in altered codons, leading to a missense mutation.
• Similarly, insertion of an extra nucleotide can shift the reading frame, modifying the codon and resulting in a different amino acid being incorporated.
• Overall, missense mutations alter the structure and nucleotide sequence of the chromosome, which subsequently modifies the mRNA and the resulting protein sequence.

Types of Missense Mutation

Missense mutations can be classified into two distinct types based on the severity of their effects: conservative and non-conservative mutations.

Conservative missense mutation

• A conservative missense mutation occurs when the mutation results in the substitution of an amino acid with another that has similar chemical properties and biological function.
• Conservative missense mutations are generally less severe, and while they may lead to a reduction in protein function, the impact is often minimal.
• In certain cases, the altered protein may still function sufficiently or even improve the organism’s adaptation, potentially increasing its fitness within an ecosystem.
• Because of this, conservative missense mutations can act as a mechanism of natural selection, helping specific organisms or populations better survive changing environmental conditions.
• The functional changes caused by conservative mutations are usually mild and may sometimes prove beneficial rather than harmful.

Non-conservative missense mutation

• A non-conservative missense mutation involves the substitution of an amino acid with one that is chemically and functionally very different from the original.
• A typical example is when a non-polar amino acid is replaced with a polar one, drastically altering the protein’s characteristics.
• Non-conservative missense mutations are more severe and often result in significant disruptions to the amino acid sequence and the structure of the resulting protein.
• These structural changes can interfere with the protein’s folding and function, leading to possible loss of activity or malfunction.
• Such mutations can affect all levels of protein structure:
• Primary structure through changes in the amino acid sequence,
• Secondary structure by altering bonding patterns, impacting alpha-helices or beta-sheets,
• Tertiary structure through disruption of the overall 3D folding of the protein.
• In proteins with quaternary structure, missense mutations can prevent individual polypeptide chains from properly assembling into larger complexes.
• This interference can ultimately disrupt entire biochemical pathways, resulting in broader functional consequences for the organism.

Applications of missense mutation

• Missense mutations can impact genes that play critical roles in the development and progression of various diseases, making them significant in disease pathogenesis.
• Induced missense mutations are being explored in molecular therapy as a strategy to treat or prevent certain genetic disorders by modifying specific gene functions.
• Mutagens can be deliberately applied to cancer cells to induce missense mutations that disrupt essential proteins within the cells, leading to their destruction and potential therapeutic effects.
• In natural environments, missense mutations may provide beneficial changes that enhance the survival and adaptability of organisms within ecosystems.
• Under controlled laboratory conditions, missense mutations have been utilized in mutation breeding to produce new and improved crop varieties with desirable traits.
• Missense mutations are valuable tools in molecular biology research, allowing scientists to investigate protein stability, protein-protein interactions, and the characteristics of various enzymatic active sites.

Examples of missense mutation

• Sickle cell anemia serves as a classic example of a missense point mutation, where a single nucleotide change leads to the incorporation of a different amino acid in the protein.
• This amino acid substitution alters the overall structure of the hemoglobin protein, significantly affecting the shape and function of red blood cells.
• As a result, the red blood cells acquire an abnormal, sickle-like shape, impairing their ability to efficiently carry oxygen throughout the body.
• These misshapen cells are also prone to causing blood clotting and vascular blockages, contributing to various health complications.
• The mutation occurs at an upstream position in the gene responsible for encoding amino acids that form proteins within the red blood cell membrane.
• The altered nucleotide sequence produces a different amino acid, which directly leads to changes in the structural integrity of the blood cell.

References

• Zhou, X., et al. (2005). Classification of missense mutations of disease genes. Journal of the American Statistical Association, 100(469), 51–60. https://doi.org/10.1198/016214504000001817
• Hijikata, A., et al. (2017). Decoding disease-causing mechanisms of missense mutations from supramolecular structures. Scientific Reports, 7(1), 8541. https://doi.org/10.1038/s41598-017-08902-1
• Zhang, Z., et al. (2012). Analyzing effects of naturally occurring missense mutations. Computational and Mathematical Methods in Medicine, 2012, Article ID 805827. https://doi.org/10.1155/2012/805827
• Biology Dictionary. (n.d.). Missense Mutation. Retrieved from https://biologydictionary.net/missense-mutation/