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Gene & Protein in Disease Sickle cell disease’s journey

E6V resulting from a missense mutation on the beta chain a patient experiences vaso-occlusive crisis, severity of
gene on both chromosomes, resulting in sickle-shaped complications, rate of hemolysis, age of onset, to name
erythrocytes. SCD can also lead to a host of complications, a few. This is because of the variable expressivity of SCD
1-3
including acute chest syndrome (ACS), avascular necrosis, even among genotypically similar patients and even among
stroke, pulmonary hypertension, splenic sequestration, homozygous individuals, which has been attributed to
gallstones, deep vein thrombosis (DVT), pregnancy modifier gene effect, social factors, and environmental
complications, and end-organ damage. Complications factors. For instance, increasing levels of fetal hemoglobin,
4,5
are of varying complexities and can be as grave as life- coinheritance with thalassemia, and certain other genetic
threatening. Treatment options available were mainly used factors are known to potentially alleviate complications,
for symptomatic relief, better well-being of the patient, while on the other hand, inheritance of thrombophilic
containment of complication recurrence as well as decrease genetic factors may accentuate them because of the
in mortality rates. These have evolved into curative enhanced hypercoagulable state. 9-17 Figure 1 summarizes
4-6
treatment options such as stem cell transplantations and the sequence of events that highlight the pathophysiology
gene therapy. The present review provides an update about of SCD. While polymerization results in the sickling of
the disease, its complications, and implications on the RBCs, the pathophysiology of complications also involves
community, as well as a historical tracking of the evolution vascular endothelial dysfunction, resulting in a pro-
of treatment options up to modern-day gene therapy. inflammatory milieu and an inflammatory response. The
inflammatory response activates signaling pathways in
2. Classification RBCs through activation of adhesion receptors. Hypoxia

The predominant type of SCD is the homozygous HbSS and stress are also known to modulate the RBC signaling
also called sickle cell anemia. The next most common type pathways by increasing the formation of deoxy-Hb S. 13,18-23
of SCD is HbSC, which is a coinheritance of HbS and HbC. An intrinsic mechanism heightening the complications
Sickle beta thalassemia (HbS/βo or HbS/β+) results from in SCD involves the scavenging of nitric oxide by the free
coinheritance with beta-thalassemia and, depending on hemoglobin released during hemolysis. 24,25 Sickle RBCs
the genetic defect on the beta thalassemia component, is have lower activity of arginase-1, the enzyme necessary
mild or as severe as HbSS. 7 for nitric oxide synthesis, blocking de novo nitric oxide
3. Epidemiology synthesis. Further, the cell-free plasma hemoglobin
limits nitric oxide bioavailability 26,27 and also leads to the
Globally, millions of individuals are affected by SCD, and generation of reactive oxygen species (ROS). 28
it is common among those whose ancestry is from the
The role of polymerization-induced ion channel
malaria-affected regions of the world, namely, Sub-Saharan activation has been implicated in a vicious cycle of
Africa, South America, the Caribbean, Central America, polymerization–ion channel activation–polymerization,
Saudi Arabia, India, and Mediterranean countries such eventually leading to hemolysis. Loss of potassium ions from
as Turkey, Greece, and Italy. In the US, where around
100,000 individuals are affected by SCD, 90% of the the RBCs and cellular dehydration follow the activation of
2+
+
-
affected individuals are from the non-Hispanic or African the K -Cl cotransport system and the Gardos channel (Ca -
+
28
American population (one in 365 births), and 3 – 9% are dependent K channel). This is ensued by an increase in
the concentration of erythrocytic hemoglobin that triggers
Hispanic (one in 16,300 births) or Latinos. 8
more deoxygenated-Hb polymer formation. The resulting
The gene frequency is highest in Western Africa where changes in sequence – denaturation of hemoglobin,
the carrier frequency for HbS is 25 – 30% and where the accumulation of hemichromes on the inside of the cell
prevalence of HbSC is also maximum. Around one in 13 membrane next to cytoskeletal proteins (e.g., Band 3),
7
Black or African American births is a carrier. 8 loss of heme, and release of Fe – create an oxidizing
3+
micromilieu. Subsequently, disruption of the membrane
4. Pathophysiology phospholipid asymmetry and clustering of anti-band 3 IgGs
SCD is the most common monogenic disorder caused by on cytoskeletal Band 3 protein due to negative charges on
point mutation worldwide, with significant variation in anionic phosphatidylserine exposed to the cell surface
9,10
disease manifestation due to several influencing factors, take place. These changes lead to erythrophagocytosis by
and the coinheritance of which can alter the severity of macrophages and the production of microparticles. 29,30 The
symptoms. 9-16 Although polymerization is identified as the role of other factors, namely, coexisting hypercoagulability
root cause of the pathogenesis in SCD, this alone cannot or concomitant inheritance of thrombophilic genetic
entirely explain the pleiotropy of SCD, namely, how often variants, intervening environmental factors, infections,

Volume 4 Issue 1 (2025) 2 doi: 10.36922/gpd.4361