Genetics of sickle cell

Sickle cell disease (SCD) is an autosomal (could affect both male and female) recessive inherited disorder that is caused by genetic mutation in the β hemoglobin (as hemoglobin has 2 subunits: 2 α chains and 2 β chains) gene found on chromosome 11. Hemoglobin transports oxygen from lungs to other parts of the body such as liver, muscle etc. So mutation in hemoglobin (HbB) gene leads to the formation of sickle shaped abnormal hemoglobin S (HbS) or sickle hemoglobin that results in sickle cell disease or sickle cell anemia. Red blood cells with normal hemoglobin (HbA) can smoothly move through the blood vessels but HbS containing blood cells cannot move normally and become stiff, harder, less flexible and pile up and block the flow of blood through vessels. This blockage results in damaging of vital tissue and organs (vasoocclusion) such as lungs, spleen, kidney and liver and causes related pain. Also the sickle or crescent shaped red blood cells polymerize at reduced oxygen tension and die prematurely that results in hemolytic anemia or sickle cell anemia [1].

SCD is a monogenic disorder that results from the missense mutation that substitutes thymine for adenine in the 6th codon of the β chain gene (GAG to GTG) that causes coding of glutamic acid by valine at 6th amino acid position (Glu6val) of the β chain of hemoglobin [2]. Other types of SCD such as sickle hemoglobin C disease (HbSC) and sickle β thalassemia (HbS β) result from coinheritance of HbS with other abnormal β hemoglobin chain variants. SCD is recessive genetic disease i.e. 2 genes for the HbS must be inherited from the parents in order to get the disease. If the person has just one copy of the mutated gene and one normal gene then they are sickle cell trait (who are mostly normal but usually carrier of the SCD) but if the individual has 2 copies of mutated gene (Hb S) that results in SCD. When both parents are sickle cell trait then their child has 25% chance to have two defective genes and suffer from SCD, 50% chance to have one defective gene and develop sickle cell trait and 25 % chance to inherit two normal genes and being unaffected by the gene mutation and diseases [3].

Due to its shape and increased stickiness sickle cells/sickle RBCs adhere to endothelium and express a bunch of adhesion molecules such as CD36, CD18, ICAM 4 (intercellular cell adhesion molecule), P selectin etc. which causes increased microvascular transit times and vaso occlusion. Sickle RBC survives for only 10-20 days (where normal RBCs survives for 90-120 days) and then hemolysis occurs intravascularly that results in releasing of plasma free hemoglobin (PFH) and arginase to plasma [4]. These cause endothelial injury including proinflammatory stress, scavenging NO (nitric oxide) and degradation of arginine (substrate for NO synthesis) which results in low level of NO production and development of pulmonary artery hypertension and severe acute chest syndrome (which is the major cause of mortality for SCD patients). As vaso occlusion damages the spleen of people with SCD they have very low level of immunity (because of low level of serum IgM molecule) and they have increased risk of certain types of bacterial infection such as Mycoplasma pneumoniae, E. coli, Staphylococcus aureus etc. Children with SCD have painful spleen enlargement due to large number of sickle cells which is known as ‘splenic sequestration’ and they also have dactylitis (pain and swelling in hand and feet) [5].

Hemoglobin electrophoresis/cellulose acetate electrophoresis, isoelectric focusing (higher resolution), HPLC (High performance liquid chromatography) are the procedures for diagnosis of SCD. Treatment of SCD includes regular blood transfusion, antibiotics, gene therapy/gene editing, bone marrow transplantation from healthy genetically compatible sibling donor, and hematopoietic stem cell transplantation in severe cases. A new drug called Hydroxycarbamide/hydroxyurea (brand name Droxia which is FDA approved) which is basically an antitumor drug is currently used for SCD [6]. This drug stimulates fetal hemoglobin (that is found only in newborns) production which helps to prevent the sickling of red blood cells and cause improved red cell survival and reduction of white blood cell, reticulocyte and platelet counts. But this drug has significant toxicity including myelosuppression so patients treated with this drug should be monitored closely with routine CBCs and reticulocyte count. Recently Global Blood Therapeutics from South San Francisco developed a pill named gbt440 which can prevent the sickling of red blood cells [7].

References:

1. http://sickle.bwh.harvard.edu/scd_inheritance.html
2. http://emedicine.medscape.com/article/205926-overview#a7
3. http://www.news-medical.net/health/Sickle-Cell-Disease-Genetics.aspx
4. https://www.nhlbi.nih.gov/health/health-topics/topics/sca/
5. https://www.ncbi.nlm.nih.gov/books/NBK1377/
6. https://www.genome.gov/10001219/learning-about-sickle-cell-disease/
7. https://www.scientificamerican.com/article/genetic-treatments-for-sickle-cell/