Molecular and Cellular Medicine

Week 4: Nucleotide and Protein Structure and Function

Sickle Cell Disease

Joel Hockensmith, PhD

1. Recognize that the structure of biochemical building components (e.g. proteins) effect the final composite structure (e.g. cell).

When HbS molecules polymerize, they cause the cell to take on a sickle shape.

2. Understand the relationship between nucleic acid sequence and the resulting protein sequence (i.e. when will nucleotide changes result in protein sequence changes).

Nucleotide changes will result in protein sequence changes if it changes which tRNA presents to the mRNA. For instance, changing AUG to AUC will change the amino acid from methionine to isoleucine, whereas a change from UCU to UCG won't change the amino acid sequence at all.

3. List amino acid substitutions which might reasonably be expect to be non-conservative for the protein structure and therefore result in changes in protein shape and/or function.

Substitutions that change the type of amino acid in a sequence will likely change the protein shape or conformation. For instance, exchanging valine (a non-polar amino acid) for aspartic acid (a charged amino acid) will result in a very different protein folding, and will likely inactivate the protein.

4. Appreciate that many genetic variants have no demonstrable effect on function (i.e. lack pathogenicity).

Only 9 of the 1040 known variants are pathological.

5. Describe the physical anomaly that leads to sickling by the red blood cell.

When the HbS is in its deoxyform, it tends to polymerize due to hydrophobic interactions with other HbS in the cell. This results in a chain form, which causes the red blood cell to sickle and to loose much of its flexibility.

6. Relate the physical properties of the normal red blood cell and the sickle cell to the pathophysiology observed clinically for a patient in sickle cell crisis.

A normal red blood cell is elastic, and can distort to fit through the smaller blood vessels in the body. The sickle cell, while taking on a new sickle shape, also loses its elasticity, making it much more difficult to get through those small vessels. This results in the accumulation of blood cells, reducing the oxygenation of tissues, resulting in pain.

7. Identify the organ often suffering severe damage in Sickle Cell Disease (SCD) and how deterioration of that organ leads to increased susceptibility to other diseases.

The spleen is one of the organs suffering the most severe damage in SCD because the blood vessels running through the spleen are small, forcing red blood cells to distort in order to move through them. In sickle cell patients, the red blood cells cannot distort easily, so there is often an accumulation of blood in the spleen. Eventually, this often results in the removal of the organ. The spleen plays a key role in the function of the immune system, so those without a spleen, or with a damaged spleen, are more susceptible to diseases due to the inability of the spleen to filter microorganisms from the bloodstream.

8. Compile a list of clinical symptoms for Sickle Cell Disease (SCD).

Neurologic injury, psychosocial issues, growth retardation and delayed puberty, leg ulcers, pulmonary complications, retinopathy, shortness of breath, dizziness, headache, coldness in the hands and feet, pale skin, chest pain, jaundice, and splenic sequestration.

9. Know how the following terms relate to SCD: Hemolytic Crisis; Splenic Sequestration; and Aplastic Crisis.

Splenic Sequestration – acute, painful enlargements of the spleen due to lack of blood flow through the spleen (and thus the buildup of blood). The abdomen becomes bloated and very hard. If not treated, patients may die within 1-2 hours due to circulatory failure.

Hemolytic Crisis – an infarction caused by the accumulation of sickle cells in the tissue resulting in lack of blood flow. Characterized by acute severe pain.

Aplastic Crisis – An infection with human parvovirus B19 (fifth disease) can result in a lowered blood production, resulting in a more severe anemia.

10. Identify a disease for which SCD provides some survival advantage.

Malaria. The parasite induces a low-oxygen state, increasing the likelihood of the cell to sickle in those with sickle cell trait (heterozygous for sickle cell disease), marking those cells for destruction before the parasite can complete its life cycle.

11. Describe the method and prevalence of testing for SCD in newborns.

As of 2008, all newborns born in the US are screened for sickle cell as a part of their newborn screening. A heelstick is performed (or cord blood collected) and blood collected on filter paper. This is then put through electrophoresis, thin-layer processing, or HPLC. Neonatal blood transfusions can affect the results.

12. Identify treatment options for SCD differentiating between those for acute and chronic treatment.

Transfusions are available to dilute the HbS concentration in the blood (chronic), nitric oxide to dilate the blood vessels to help maintain good blood flow (acute), bone marrow transplant to remove the ability of the body to produce the sickled cells (chronic), sodium buytrate to induce the production of fetal hemoglobin (chronic), hydroxyurea to upregulated the synthesis of fetal hemoglobin (chronic).

13. Identify iatrogenic conditions (adverse reactions) resulting from SCD treatments.

Transfusion complications include alloimmunization, delayed hemolytic transfusion reaction, iron overload, and transmission of viral illness. Excessive nitric oxide use can result in low blood pressure. Hydroxyurea is a chemotherapeutic agent, so it can cause hematopeoetic depression, increased risk of leukemia, and opportunistic infections due to neutropenia.

14. Grasp the concept that the severity of disease is comprised of a complex array of factors and know the factors that are relevant for SCD.

The underlying cause of problems in sickle cell disease is narrow blood vessels in which the sickled cells cannot squeeze through. Each person with sickle cell will likely have a different pattern of vaso-constrictive blood vessels, and thus a different set of symptoms. Illnesses which affect blood circulation pathways (such as obesity, diabetes, etc) can expedite the onset of SCD symptoms, while stress, trauma, and other external conditions may also affect the wide presentation of symptoms.

15. Be familiar with treatments that do not cure SCD but are targeted towards alleviating the symptoms of SCD and/or mitigating the iatrogenic effects of SCD therapies.

The only cure for SCD is bone marrow transplant. All others are aimed at alleviating symptoms, either by reducing the number of sickle cells (through upregulation of fetal hemoglobin, etc), or by assisting with the transport of cells through blood vessels (by vasodilation).