A case study of the effects of mutation: Sickle cell anemia
Sickle-cell disease (SCD) is a group of blood disorders typically inherited from a person’s parents. The most common type is known as sickle-cell anaemia (SCA). It results in an abnormality in the oxygen-carrying protein haemoglobin (hemoglobin S) found in red blood cells. This leads to a rigid, sickle-like shape under certain circumstances.
The disease is caused by a mutated version of the gene that helps make hemoglobin — a protein that carries oxygen in red blood cells. People with two copies of the sickle cell gene have the disease. People who carry only one copy of the sickle cell gene do not have the disease, but may pass the gene on to their children.
The mutations that cause sickle cell anemia have been extensively studied and demonstrate how the effects of mutations can be traced from the DNA level up to the level of the whole organism. This gene occurs in chromosome 11. Several subtypes exist, depending on the exact mutation in each haemoglobin gene.An attack can be set off by temperature changes, stress, dehydration, and high altitude. A person with a single abnormal copy does not usually have symptoms and is said to have sickle-cell trait. Such people are also referred to as carriers.Diagnosis is by a blood test and some countries test all babies at birth for the disease. Diagnosis is also possible during pregnancy.
The mutation causing sickle cell anemia is a single nucleotide substitution (A to T) in the codon for amino acid 6. The change converts a glutamic acid codon (GAG) to a valine codon (GTG). The form of hemoglobin in persons with sickle cell anemia is referred to as HbS. The nomenclature for normal adult hemoglobin protein is HbA1. Adult red blood cells also carry another minor form of adult hemoglobin (about 2% of the total) identified as HbA2. The HbA1heterotetramer is composed of two α-globin peptides and two β-globin peptides. The HbA2 heterotetramer is composed of two α-globin peptides and two δ-globin peptides. The human β-globin gene cluster contains several genes whose 5′ to 3′ orientation on chromosome 11 reflects the ontogeny of their expression from embryonic globin [episilon (ε) gene], to fetal β-globin [gammaG (γG) and γA genes], to adult β-globin [weakly the delta (δ) gene followed by the β gene]. The β-globin gene (HBB) is located at 11p15.5 and is composed of 3 exons that encode a 147 amino acid protein.
The underlying problem in sickle cell anemia is that the valine for glutamic acid substitution results in hemoglobin tetramers that aggregate into arrays upon deoxygenation in the tissues. This aggregation leads to deformation of the red blood cell into a sickle-like shape making it relatively inflexible and unable to traverse the capillary beds. This structural alteration in the red blood cell can easily be seen under light microscopy and is the source of the name of this disease. Repeated cycles of oxygenation and deoxygenation lead to irreversible sickling.
Sickle cell anemia is an autosomal recessive disorder. This means that in order for full disease symptoms to manifest in an individual they must carry two copies (homozygous genotype = SS) of the HbS gene. However, individuals who are heterozygous (genotype = AS) have what is referred to as sickle cell trait, a phenotypically dominant trait. Although AS individuals are clinically normal their red blood cells can sickle under very low oxygen pressure, e.g. when at high altitudes in airplanes with reduced cabin pressure. Because of this phenomenon, AS individuals exhibit phenotypic dominance yet are recessive genotypically.