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Diseases associated with missense mutations

Missense mutations, also referred to as point mutations, are a type of single-nucleotide polymorphism (SNP).  A missense mutation is considered non-synonymous because it usually results in a non-conservative amino acid change to the polypeptide, meaning that the original amino acid is replaced with one that is different. This change to the amino acid sequence results in changes to the structure and/or function of the three-dimensional protein product.   

Diseases caused by missense mutations

Cystic Fibrosis

Cystic fibrosis is a heritable single-gene disorder. It is characterized by an autosomal-recessive inheritance pattern, meaning an individual must have two defective copies of the gene for the cystic fibrosis disease phenotype to occur — otherwise, an individual who possesses a single defective copy along with a normal functioning copy will not have cystic fibrosis but will be a carrier. The disease is caused by a mutation to the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR). The CFTR is an essential transmembrane protein that is found in a vast majority of human cell types. One of its main function is to transport chloride ions across the membrane between the cell cytoplasm and the outer surface of the cell. This ion transport is important for many cell types, particularly for organs with epithelial cells that are exposed to the body’s outer environment. Many of these organs and organ systems produce fluids such as sweat, mucus and digestive fluids. The viscosity of these fluids depends on the chloride concentration, as it affects the diffusion of water across the membrane. Therefore, the CFTR protein plays a critical role in these fluids having the correct viscosity. Because the mutation to the CFTR gene usually causes a loss-of-function to the CFTR protein, the cystic fibrosis phenotype is associated with functional deficits in multiple organs and organ systems — including the lungs and respiratory system, the pancreas and the digestive tract, the male gonads and the reproductive system, and the endocrine system. For example, thicker mucus on the surface of lung epithelial cells makes it more difficult for clearance of mucus and makes the surface a hotspot for bacteria — recurring infections are one of the main traits of cystic fibrosis.   

At a genetic level, the CFTR gene is relatively large and numbers close to 230,000 base pairs. Given its size, close to 2000 different disease-causing mutations have been identified, of which 795 of them are missense mutations. Different missense mutations cause unique defects to the CFTR protein, and when including environmental factors, the nature of the manifestation of cystic fibrosis can greatly vary depending on the mutation and the way it affects the CFTR protein. Overall, these missense mutations can be deleterious to the CFTR protein in the following ways:

• during synthesis, the CFTR protein folds improperly
• improper use of ATP (the CFTR protein cannot function without using energy)
• the CFTR protein does not allow chloride ions to pass through correctly
• reduced life of the CFTR protein, resulting in quicker degradation and deficiency of the CFTR protein

It is important to note that statistically, over two-thirds of cystic fibrosis cases are due to the same ΔF508 deletion of three nucleotide base pairs at the 508th codon — not caused by any one of the diverse missense mutations found. 

Colour Blindness

Colour-blindness is an eye disorder defined by either an inability to differentiate between certain colours or by the loss of colour vision entirely. The disorder is characterized by defects in one of the three retinal cone cells — the photoreceptor cells responsible for colour vision located in the retina of the human eye. Humans experience trichromatic vision, because each type of cone cell specializes in processing and relaying information to the optic nerve regarding a different part of the visible light spectrum. As a result of colour vision being divided into three distinct subtypes, colour blindness is also divided into three distinct disease genotypes and phenotypes.

In the human genome, each cone cell is related to a different genetic location and each subtype of the colour blindness disorder is caused by mutations (of which some are missense mutations) to these distinct regions of the genome. The subtypes of colour blindness are called protanopia (red colourblindness), deuteranopia (green colourblindness), and tritanopia (blue colourblindness). The genes responsible for the cone cells that process red and green colour, called OPN1LW and OPN1MW respectively, are located close to each other on the X-chromosome, making protanopia and deuteranopia X-linked genetic disorders. The gene responsible for blue colour vision, called OPN1SW, is located on chromosome 7 and follows an autosomal dominant inheritance pattern. 

With respect to the possible missense mutations that can cause colour blindness, each subtype of the disorder is characterized by different mutations. Protanopia can be caused by a missense mutation to the X chromosome that results in a glycine to glutamic acid amino acid substitution at the 338th amino acid number. Deuteranopia can be caused by a missense mutation to the X chromosome that results in either an asparagine to lysine substitution at the 94th amino acid number or an arginine to glutamine substitution at the 330th amino acid number. Tritanopia, for which the associated gene OPN1SW is located on chromosome 7, can be caused by one of two different missense mutations resulting in a non-conservative amino acid change.

Sickle-cell anemia

Sickle-cell anemia is a subtype of sickle-cell disease, and is characterized by an autosomal recessive inheritance pattern. It is classified by a specific change to the structure of the oxygen-carrying haemoglobin protein in red blood cells. The haemoglobin protein in part consists of two β-globin chains. The missense mutation responsible for sick-cell anemia occurs in the gene that codes for these β-globin chains. The missense mutation is a single base pair A > T at the 6th position in the peptide chain, and results in an amino acid substitution from glutamic acid to valine. Haemoglobin with this mutation is denoted as HbS, as opposed to the normal HbA protein.  

The amino-acid substitution causes the mutant HbS protein to behave differently under stressful, low-oxygen conditions. In a single red blood cell (RBC), the β-globin chains of two different mutation HbS proteins fuse under low oxygen concentrations. This fusion results in an irreversible change to the overall structure of the RBC, which assumes a “sickle-like” shape. The elasticity and mobility of the RBC is greatly reduced, and it is unable to pass through capillaries. This decrease in mobility and elasticity leads to chronic episodes of occlusion (i.e. blockage of blood pathways). These recurring events lead to restricted blood and oxygen supply to essential organs, and overall damage to these organs — including the kidneys, bones, lungs, and brain — ensues. In addition, the sickle-shaped, mutant RBC’s have a greatly reduced lifespan from an average of 120 days to between 10-20 days. Consequently, the RBC’s die at a much faster rate than they are produced and a shortage in RBCs results — this is where the anemia stems from.