Question

An athletic 21-year old, African-American male in good health joined a climb partway up Mt. Rainier in Washington. Despite his overall fitness, the rigors of the climb were far greater than he expected, and he found himself breathing heavily. At an elevation of 6000 feet, he began to feel twinges of pain on the left side of his upper abdomen. At 9000 feet, the pain worsened to the point that he stopped climbing and descended the mountain. The pain became very severe during the days after his climb. He went to the emergency room, where tests revealed a disorder in his red blood cells due to an abnormal form of the protein hemoglobin. The patient had a condition called sickle-cell trait. Such individuals are carriers of the gene that causes sickle-cell disease. How does a gene mutation result in a change in the quaternary structure of hemoglobin and how does this impact a person's blood when exposed to low oxygen?

Answer 1

Sickle cell Trait and disease.

Hemoglobin is a protein located on the RBC and its role is to carry oxygen to tissues. There are many forms of hemoglobin. In adults, it is called HbA. The adult HbA has two alpha chains and two beta chains. Each alpha chain has 141 amino acids and beta chains have 146 amino acids respectively.

The quarternary structure of hemoglobin contains these alpha and beta subunits together connected by relatively weak non-covalent forces such as van der waals, electrostatic and hydrogen bonds.

Sickle cell hemoglobin.

It is the most type of hemoglobinopathy wherein abnormal hemoglobin causes sickling or distortion in the shape of the RBC.

Sickle cell disease and trait.

When in the normal structure of hemoglobin, due to gene mutation, the amino acid glutamic acid in the 6 th position of beta chain is replaced by valine; sickle cell disease or trait results. In homozygous state, (when both the alleles coding for HbS;SS)disease with clinical manifestation results in normal conditions while in heterozygous state(Hb A and HbS; AS), the person would be asymptmatic except in hypoxic conditions like how this 21 year old athlete was in.(high altitude).

The heterozygous state is very common in central and west africa and east and central parts of India as well

What happens in sickle cell disease and trait ?

The substitution of glutamic acid(hydrophilic) by valine(hydrophobic) causes a localized stickiness in the surface of the molecule. When the hemoglobin molecule is deoxygenated, many such molecules will adhere together and polymerise which results in the sickling. This is not seen when a normal adult hemoglobin(HbA) is in deoxygenated state.

These sickled cells plugs the small capillaries and can lead to blockage of blood vessels which can lead to infarction of organs like spleen.

In this case the athelte shows symptoms of twinges of pain in the upper left abdomen, which is a sign of splenic infarction.

The athelete is in heterozygous condition meaning, 50% of his Hb in RBC is normal which explains why he was symptomatic in normal condition. Altough onec at a higher altitude, hypoxia causes the disease to manifest since in deoxygenated state, the affected RBCs undergo sickling.