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7 - The sickling disease page 2
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2. What causes sickle cell anaemia? Link to the Medical Research Council web site
Sickle cell haemoglobin
Haemoglobin molecules are made up of four polypeptide chains known as globins. Each globin chain is attached to an iron-containing haem molecule, which is the part that carries oxygen. Intermolecular attractions between amino acids in adjacent globin chains hold the four chains together in the quaternary structure. Under conditions of high concentration of oxygen, such as in the lungs, haemoglobin associates readily with oxygen. In the body tissues, where oxygen concentrations fall, the affinity of haemoglobin for oxygen is much less and oxygen is released.

Figure 3

Figure 2. The haemoglobin molecule contains two a-globin chains (pattern A) and two ß-globin chains (pattern B). Two of the four haem molecules are visible (pattern C).




Different haemoglobins are synthesised in the adult and the fetus, each adapted to its particular oxygen requirements. Adult haemoglobin (HbA) has two alpha (a) globin chains associated with two beta (b) globin chains as in Figure 2. In fetal haemoglobin (HbF), the two a-chains are combined with two gamma (g) globin chains. The b- and g-globin are part of a linked cluster of genes on chromosome 11; similarly the genes for a-globin are in a cluster on chromosome 16.
Certain base sequences within the globin genes are regulatory, and help to co-ordinate changes in globin gene activity during development. During the months after birth, for example, the synthesis of fetal haemoglobin declines as the activity of the g-globin gene is suppressed and the a-globin gene is `switched on'. This allows synthesis of adult haemoglobin.
Sickle cell anaemia results from a mutation involving a single nucleotide in the sixth codon of the gene for b-globin. This mutation leads to a change in just one amino acid. The polar amino acid glutamic acid in normal b-globin chains is replaced by the non-polar amino acid valine.
Consequently, sickle cell haemoglobin (HbS) replaces normal adult HbA in the red blood cells. This apparently trivial alteration to the b-globin gene alters the quaternary structure of haemoglobin which, in turn, has a profound influence on the physiology and well-being of an individual.

A closer look at haemoglobin S

Haemoglobin S (HbS) is less efficient at carrying oxygen than normal haemoglobin. It is also much less soluble and begins to crystallise as the oxygen concentration falls, as it does in the capillaries of the tissues. The HbS molecules polymerise, arranging themselves in long, parallel fibres within the red blood cells. These fibres are stabilised by interactions between the substituted valine and hydrophobic regions on adjacent HbS molecules. This causes the red blood cells to become sickle, or crescent, shaped.

In their lifetime's passage of about 100 miles around the body, the red blood cells go through a cycle of sickling and desickling, eventually becoming irreversibly sickled. Unavoidable damage is caused to the red blood cell membrane resulting in lysis of these fragile cells after a lifespan of merely a few days (compared with the normal lifespan of 120 days). Chronic haemolytic anaemia results.
Sickled cells are also relatively inflexible and rigid and tend to form aggregates, so increasing the viscosity of the blood. Small capillaries become blocked, which deprives tissues of their blood supply and leads eventually to death of the tissue. Almost any organ can be involved in this process, which may be excruciatingly painful, although bones are particularly susceptible. If the blood vessels supplying the brain are affected, this can cause a stroke, or if the sickle cells sequester in vessels of the lungs, this can lead to a gradual deprivation of oxygen, which places a severe strain on the heart. Secondary infections frequently follow repeated blockage of blood vessels.

Genes and proteins

Haemoglobin S is coded for by the sickle cell allele S, which is an example of an autosomal mutation. Individuals who are homozygous for the mutant allele suffer from sickle cell anaemia. Heterozygote carriers are phenotypically normal (their cells sickle only at very low oxygen concentrations), and are said to have the sickle cell trait.

Questions 1 and 2

1. Using A for the normal haemoglobin allele and S for the mutant sickle cell allele, give the genotype for an individual with:

  1. normal haemoglobin
  2. sickle cell trait
  3. sickle cell anaemia.

 2. Below are genetic diagrams to illustrate the genotypes and phenotypes of children born to the following parents:

ia) normal haemoglobin x sickle cell trait ib) sickle cell trait x sickle cell trait

 In each case what is the probability of a child being born:

  • with sickle cell anaemia?
  • a carrier for the mutant sickle cell allele?

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