Understanding Genetic Mutations

Differences in nucleotide sequences, either between two individuals or among all individuals within a population, constitute genetic variation.

Differences that arise in nucleotide sequences and lead to a structural change in the proteins they encode are called mutations. A change in the nucleotide sequence is known as a mutation.

A mutation may be defined as a permanent transmissible change in the nucleotide sequence of a chromosome, usually in a single gene, which may lead to loss or change of the normal function of the gene. An incidence of mutation is rare, occurring in less than 1% of a given population.

A mutation can have a significant effect on protein production or function because it can alter the amino acid sequence of the protein that is coded by the DNA sequence in a gene. Examples of mutations are point mutations which comprise insertions, deletions, transitions and transversions.

Two types of events can cause a point mutation: chemical modification of DNA, which directly changes one base into another, or a mistake during DNA replication that causes, for instance, the insertion of the wrong base into the polynucleotide during DNA synthesis.

Transitions are the most common type of point mutations and result in the substitution of one pyrimidine (C–G) or one purine (A–T) by the other.

Transversions are less common, where a purine is replaced by a pyrimidine or vice versa.

The functional outcome of mutations can vary very significantly. For example, a single-point mutation can change the third nucleotide in a codon and not change the amino acid that is translated, or it may cause the incorporation of another amino acid into the protein, a phenomenon, known as missence mutation.

Missense mutations result from substitutions of one or more nucleotides in such a way as to change the primary sequence of the encoded protein. They alter the function of the protein by changing its primary structure.

The functional effect of a missence mutation varies greatly depending on the site of the mutation and the importance of the protein in relation to health.

A missence mutation can have no apparent effect on health or it can result in a serious medical condition. For example, sickle cell anemia Opens in new window is due to a missence mutation of the β-globin gene: a glutamine is changed to valine in the amino acid sequence of the protein.

This has drastic effects on the structure and function of the β–globin protein, which causes aggregation of deoxygenated hemoglobin and deformation of the red blood cell.

A nucleotide change can also result in the generation of a stop codon and no functional protein will be produced, a phenomenon known as nonsense mutation.

A nonsense mutation introduces a premature stop codon into a gene, resulting in a truncated gene product that can display alterations in function and be unstable.

Another form of mutation is frameshift mutation which involves small deletions or insertions of bases that alter the reading frame of the nucleotide sequence; hence, the amino acids in the peptide sequence.

Frame shift mutations occur when codons of a gene are read in the wrong reading frame. These mutations typically cause abnormal protein structure because of the introduction of out-of-frame termination codons, which lead to premature termination of proteins.

Mutations in introns and exons cause splicing errors that also lead to alterations in protein structure or premature termination.

Finally, mutations in the promoters or enhancers of genes can lead to alterations in the levels of expression of a protein or the temporal or spatial patterns of gene expression of a protein.

Mutations in single genes lead to monogenic cardiovascular diseases. For example, although the primary defect in familial hypercholesterolemia Opens in new window is a deficit of low-density lipoprotein receptors (LDLRs), more than 600 mutations in the LDLR gene have been identified in patients with this disorder.

Similarly, hypertrophic cardiomyopathy Opens in new window, an autosomal dominant disease Opens in new window, is caused by mutations in the genes encoding proteins of the myocardial contractile apparatus.

Other monogenic cardiovascular disorders include familial long-QT syndrome Opens in new window, venous thrombosis Opens in new window caused by factor V Leiden, and inherited forms of hypertension.

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    Adapted from Thompson & Thompson Genetics in Medicine E-Book By Robert L. Nussbaum, Roderick R. McInnes, Huntington F Willard