Missense Mutations
A mutation that changes the codon from one amino acid to that for another by substitution of one base for another is a missense mutation (Figure 3.11). As shown in Figure 3.9, the second base of each codon shows the most consistency with the chemical nature of the amino acid it encodes. Amino acids with hydrophobic side chains, shown in black in Figure 3.9, have a U or a C – a pyrimidine – in the second position. With two exceptions, serine and threonine, amino acids with hydrophilic side chains, shown in green in Figure 3.9, have a G or an A – a purine – in the second position. This has implications for mutations of the second base. Substitution of a purine for a pyrimidine is very likely to change the chemical nature of the amino acid side chain significantly and can therefore seriously affect the protein. Sickle cell anemia is an example of such a mutation. At position 6 in the β‐globin chain of hemoglobin, the mutation in DNA changes a glutamate residue encoded by GAG to a valine residue encoded by GTG (GUG in RNA). The shorthand notation for this mutation is E6V, meaning that the glutamate (E) at position 6 of the protein becomes a valine (V). This change in amino acid alters the overall charge of the chain and the hemoglobin tends to precipitate in the red blood cells of those affected. The cells adopt a sickle shape and therefore tend to block blood vessels, causing sickle cell anemia with painful cramp‐like symptoms and progressive damage to vital organs.
William Warrick Cardozo.
Source: AAREG. Image from https://aaregistry.org/story/sickle‐cell‐pioneer‐willliam‐w‐cardozo/.
The peculiar shape of red blood cells in patients with sickle cell anemia was first described in 1910 but little experimental investigation had been conducted until William Warrick Cardozo published a paper in 1937 reporting a comprehensive study of the largest number of patients ever tested for the disease. Cardozo was a pediatrician whose research on sickle cell anemia was conducted during a two‐year fellowship in pediatrics at the Children's Memorial Hospital and Provident Hospital in Chicago. Cardozo's findings confirmed the heritability of the disorder and revealed that “the sickling factor remains within the cell, no matter how long preserved, as long as the cell itself remains intact.” He concluded that future therapeutic interventions would need to be interventions on the cell itself. Today, the only cure for sickle cell anemia is a stem cell or bone marrow transplant that replaces the damaged red blood cells with healthy ones.
Medical Relevance 3.2 Osteogenesis Imperfecta
Collagen is the most abundant protein in the body and a major component of the extracellular matrix. The triple helix of Type I collagen is made up of two alpha1 chains and an alpha2 chain encoded by the COL1A1 and COL1A2 genes, respectively. The repetition of glycine, the smallest amino acid, at every third position in the triple helical domain of collagen allows the formation of the triple helix. A change of one base in one of these codons in COL1A1 could cause a missense mutation and the introduction of any one of eight different amino acids at this position. These altered amino acid residues affect the structural properties of collagen, disrupting the extracellular matrix and causing the disease Osteogenesis Imperfecta. The clinical severity of the disease ranges from mild to fatal and correlates with the identity of the amino acid that replaces glycine.
Answer to thought question: Glycine is coded for by four codons: GGU, GGC, GGA, and GGG. A single base substitution in the third base will have no effect on the protein since the codon will still encode glycine. For each of the four codons GGU, GGC, GGA, and GGG we can tabulate the effect of a single base substitution in the first or second base; the unmutated codon is shown in green and the mutated base in red:
| G | G | U | coding for glycine |
| A | G | U | coding for serine |
| U | G | U | coding for cysteine |
| C | G | U | coding for arginine |
| G | A | U | coding for aspartate |
| G | U | U | coding for valine |
| G | C | U | coding for alanine |
| G | G | C | coding for glycine |
| A | G | C | coding for serine |
| U | G | C | coding for cysteine |
| C | G | C | coding for arginine |
| G | A | C | coding for aspartate |
| G | U | C | coding for valine |
| G | C | C | coding for alanine |
| G | G | A | coding for glycine |
| A | G | A | coding for arginine |
| U | G | A | coding for STOP |
