The HBB gene provides instructions for making a protein called beta-globin. Beta-globin is a component of hemoglobin. Sickle cell anemia is caused by a particular variant in the HBB gene that results in hemoglobin S (HbS). The abnormal hemoglobin S subunits stick together and form long, rigid molecules that bend red blood cells into a sickle shape. The rigid sickle-shaped cells can block small blood vessels, causing severe pain and organ damage.

Sickle cell disease (SCD) is caused by a point mutation in the β-globin gene (HBB) that results in the substitution of valine for glutamic acid at the sixth position of the β-globin chain, producing sickle hemoglobin (HbS). This mutation results in the formation of sickle hemoglobin (HbS), which has the unique feature of polymerizing on deoxygenation. The polymerization of HbS is a critical event in the pathophysiology of SCD. HbS polymers form long strands very quickly. The lengthening polymer fibers deform affected erythrocytes, reducing their flexibility and impacting rheology. This deformation of erythrocytes promotes hemolytic anemia and the obstruction of blood flow (vaso-occlusion), resulting in ischemic episodes known as crises.

Vaso-occlusive crisis (VOC) begins with increased sickling and interaction of the sickle erythrocytes with the endothelium in the post-capillary venules, either directly or by way of leukocytes adherent to the endothelium, leading to obstruction of blood flow that triggers a host of signaling cascades. Leukocytes immobilized to the endothelium form the nidus for the adherence of sickle erythrocytes, leading to vascular obstruction and local hypoxemia. As a result of VOC, hypoxemia in the vicinity of the vaso-occlusion occurs. Hypoxemia provides the positive feedback to induce polymerization of HbS in erythrocytes that have not previously been involved in the sickling process. Recurrent vaso-occlusion causes chronic disabling arthritis due to osteonecrosis affecting the joints, progressive retinopathy, chronic renal failure, increased risks for strokes, and shortened lifespan.

Sickle-cell disease (SCD) is a genetic disorder that affects haemoglobin, the molecule in red blood cells responsible for carrying oxygen.[2] SCD is caused by a mutation in the HBB gene, which provides instructions for making haemoglobin.[2] This mutation leads to the production of abnormal haemoglobin known as haemoglobin S.[2] The disease causes red blood cells to become rigid and sickle-shaped, leading to blockages in blood flow and subsequent pain and organ damage.[2]

SCD is autosomal recessive from a single point mutation in codon six of the β-globin gene (HBB) resulting in sickle hemoglobin.[4] However, an alternative approach and potentially more ideally curative is to directly correct the pathogenic sickle mutation in HBB gene, thus preserving physiologic regulation of gene expression.[4]

A single mutation from A to T in the β globin gene of hemoglobin, resulting in replacement of negatively charged glutamic acid by hydrophobic valine on the molecular surface, is responsible for sickle cell disease. The amino acid change causes polymerization of this mutant hemoglobin (hemoglobin S [HbS]) to form fibers upon deoxygenation in the tissues, the root cause of the pathology of the disease. Both the amount of fiber at equilibrium and the kinetics of fiber formation depend on the partial pressure of oxygen. The root cause of pathology in sickle cell disease is the polymerization of the mutant hemoglobin S upon deoxygenation in the tissues to form fibers.

A number sign (#) is used with this entry because sickle cell disease is the result of mutant beta globin (HBB; 141900) in which the mutation causes sickling of hemoglobin.[7] Hemoglobin polymerization, leading to erythrocyte rigidity and vasoocclusion, is central to the pathophysiology of the disease, but the importance of chronic anemia, hemolysis, and vasculopathy has been established.[7] The genetic basis of sickle cell disease is an A-to-T transversion in the sixth codon of the HBB gene.[7]

Upon deoxygenation, HbS polymerizes inside the red cell resulting in damage to the red cell membrane. Over repeated cycles of HbS deoxygenation and reoxygenation, irreversible membrane damage occurs, producing a population of rigid, poorly deformable cells. On deoxygenation, the presence of valine (Hb S) instead of glutamic acid allows adjacent Hb molecules to bind to each other. As additional binding occurs, polymerization of the Hb S molecules produces tubular fibers that distort the cell into the characteristic sickled shape. Hb S polymerization occurs when the oxygen tension within the RBC is lowered but is accentuated when RBCs are exposed to acidosis (low pH), high temperature (fever), and increased osmolality (dehydration).

What makes HbSS disease survivable and HbS/HPFH benign is the unusual kinetics of polymerization, with a marked delay period before fibers appear that allows most cells to escape the small vessels of the tissues before fibers start to form. Because the delay time is extraordinarily sensitive to oxygen pressure and intracellular Hb concentration, even small degrees of polymerization inhibition can produce large increases in the delay time, allowing many more cells to escape the tissues without sickling. The major allosteric effector for Hb is 2,3-diphosphoglycerate (2,3-DPG), and it has three effects on HbS polymerization. It binds in the cleft between the β subunits to stabilize the deoxy (T) quaternary structure and thereby decreases oxygen affinity by shifting the T-R quaternary equilibrium toward T, which promotes conditions favoring HbS polymerization and sickling.

In the homozygous form of sickle cell disease, inciting triggers (eg, hypoxia, dehydration, exposure to cold or weather changes, stress) cause hemoglobin polymerization, resulting in the sickling and increased rigidity of erythrocytes. The subsequent deoxygenation of erythrocytes, the sickling, and now damaged red blood cells attach to the endothelial wall, forming a mass comprised of leukocytes and platelets with adhesion molecules P and E selectins. The formation of these heterocellular aggregates physically causes small vessel occlusion and resultant local hypoxia. This process triggers a vicious cycle of increased HbS formation and releases inflammatory mediators and free radicals, contributing to reperfusion injury. Patients with vaso-occlusive crisis (VOC) present with moderate to severe pain, which has variable intensity and frequency.

Sickle cell disease (SCD) is a genetic disorder caused by a mutation in both copies of a person’s HBB gene.[3] This gene encodes a component of hemoglobin, the oxygen-carrying protein in red blood cells.[3] The mutation causes hemoglobin molecules to stick together, creating sickle-shaped red blood cells.[3] This can lead to blood cell rupture, anemia, recurring pain, immunodeficiency, organ damage, and early death.[3]

Sickle cell disease is a group of inherited red blood cell disorders.[6] Sickle cell disease is caused by a mutation in the hemoglobin-Beta gene found on chromosome 11.[6] In people with sickle cell disease, abnormal hemoglobin molecules - hemoglobin S - stick to one another and form long, rod-like structures.[6] These structures cause red blood cells to become stiff, assuming a sickle shape.[6] Their shape causes these red blood cells to pile up, causing blockages and damaging vital organs and tissue.[6] The sickle cells also block the flow of blood through vessels, resulting in lung tissue damage that causes acute chest syndrome, pain episodes, stroke and priapism.[6]

Sickle cell disease occurs in people who inherit two copies of the sickle cell gene, one from each parent. This produces abnormal hemoglobin, called hemoglobin S. Symptoms result when mutated red blood cells take a sickle shape, blocking blood flow and decreasing oxygen delivery. People with sickle cell disease can experience excruciating pain and organ problems.

It is also well confirmed that the oxygenated HbS (OHbS) does not participate in the polymerization, while the deoxygenated HbS (dHbS) does, which causes the shape of red blood cells sickled. After polymerization, the blood has a low oxygen affinity. For example, the main findings regarding the pH effect showed that the lowered pH over the physiological range promotes not only HbS polymerization but also RBC sickling. Hence, the chance for polymerization of HbS is increased at lower pH. Of course, the deoxygenated form of HbS takes part in polymerization reaction rapidly, but it must be remembered that the oxygen affinity and hemoglobin polymerization both are different things.

Recurrent and unpredictable episodes of vaso-occlusion are the hallmark of sickle cell disease. During vaso-occlusive episodes, abnormal adhesive interactions among erythrocytes, leukocytes, and endothelial cells contribute to microvascular blood flow obstruction and ischemic tissue injury. Polymerization of deoxygenated sickle hemoglobin (HbS) promotes erythrocyte sickling, decreased deformability, and increased viscosity, all of which contribute to vaso-occlusion. HbS polymerization is critically dependent on intracellular hemoglobin concentration and oxygen tension; polymerization is favored under low-oxygen conditions.

Sickle cell disease (SCD) is caused by mutations in the HBB gene, which encodes for the beta chain of the adult hemoglobin protein (HbA).[1] The mutated gene produces a defective beta-globin chain called hemoglobin S (HbS) that polymerizes and causes the deformation of red blood cells (RBCs) into a sickle shape, resulting in decreased RBC lifespan and hemolysis.[1] These inflexible sickle-shaped RBCs can also block the normal flow of blood in blood vessels (vaso-occlusion), depriving the tissues or organs of oxygen and leading to damage.[1] Under low oxygen conditions, this valine forms hydrophobic interactions with other hydrophobic residues on other HbS molecules, leading to HbS polymerization and the characteristic sickled RBC shape.[1]

The alpha (HBA) and beta (HBB) loci determine the structure of the two types of polypeptide chains in adult hemoglobin, Hb A. Mutant beta globin causes sickle cell anemia. The HBB gene result is associated with Hb SS disease.

Vaso-occlusive crises are believed to occur because of adherence of sickled RBCs to the vascular endothelium, adherent leukocytes, and platelets in small blood vessels. This multicellular adhesion, rather than changes in RBC morphology per se, is now thought to be the trigger for VOC, and has been shown in animal models to lead to initiation of VOC. Vaso-occlusion is a multifactorial process involving not only occlusion of small blood vessels by sickled red blood cells (RBCs) and adherent blood cells, but also large-vessel intimal hyperplasia, thrombosis, and bone marrow fat embolization, leading to hypoxia, ischemia, and tissue damage and inflammation. The pathophysiology of VOCs includes polymerization of abnormal sickle hemoglobin, inflammation, and adhesion.

Sickle cell disease (SCD) is a name for inherited blood disorders due to a change in the HBB gene.[5] A genetic variation in the HBB gene causes sickle cell disease.[5] The HBB gene has the instructions for making hemoglobin, a part of your red blood cells that carries oxygen.[5] Changes in this gene can make abnormal versions of hemoglobin, called hemoglobin S.[5] Red blood cells with hemoglobin S can become C-shaped and stick together.[5] They can get stuck as they travel through your body.[5] All of this means your tissues and organs may not get enough oxygen to work properly.[5] This can cause episodes of pain and life-threatening complications.[5]

The vaso-occlusive crisis, or sickle cell crisis, is initiated and sustained by interactions among sickle cells, endothelial cells and plasma constituents. Vaso-occlusion is responsible for a wide variety of clinical complications of sickle cell disease, including pain syndromes, stroke, leg ulcers, spontaneous abortion and renal insufficiency. Acute pain in patients with sickle cell disease is caused by ischemic tissue injury resulting from the occlusion of microvascular beds by sickled erythrocytes during an acute crisis. Obstruction of blood flow results in regional hypoxemia and acidosis, creating a recurrent pattern of further sickling, tissue injury and pain. Chronic pain occurs because of the destruction of bones, joints and visceral organs as a result of recurrent crises.

Sickle cell disease is an autosomal recessive hemoglobinopathy that affects red blood cells, causing them to adopt a sickle or crescent shaped formation when under duress.[8] This disease is caused by a single mutation to the hemoglobin beta (HBB) gene.[8] When people have one HBB gene mutation, they have sickle cell trait.[8] When a person inherits two HBB mutations from both of their parents, they have sickle cell disease.[8] There are numerous complications are associated with sickle cell disease including pain crises, acute chest syndrome and stroke.[8]

The key to the pathology of sickle cell disease is the polymerization of sickle hemoglobin (HbS), which is a point mutation of the normal hemoglobin (HbA). The polymerization of HbS occurs when the concentration of deoxy HbS exceeds the solubility. Our polymer growth rates obtained from pure HbS, HbS/HbA mixtures, and partial photolysis of HbS validate a simple linear growth rate equation including any non-polymerizing species in the activity coefficient calculation. This implies that monomer is adding to the end of the polymer one by one, not by oligomers.

A vaso-occlusive crisis (VOC), a hallmark of sickle cell disease (SCD), is an episode of intense pain related to blood vessel blockage and a lack of oxygen supply. Red blood cells containing abnormal versions of hemoglobin can take on a crescent or sickle shape. These cells are less flexible and more likely to stick to each other and to blood vessel walls, blocking blood vessels and limiting blood flow. Sickle-shaped red blood cells in people with SCD are more likely to get trapped inside small blood vessels and die prematurely. Interruptions in blood flow and oxygen supply caused by blood vessel obstruction damage tissues and trigger inflammation, creating a vicious cycle in which inflammation and blood vessel blockage continuously fuel each other, driving VOCs in people with SCD.

Sickle cell disease is caused by mutations in the hemoglobin beta (HBB) gene. The disease is characterized by sickle-shaped rigid red blood cells caused by the hemoglobin defect. Sickle cell disease is an autosomal recessive disorder.

The most common clinical manifestation of sickle cell disease (SCD) is vaso-occlusive crisis, which occurs when the microcirculation is obstructed by sickled red blood cells (RBCs). Obstruction of blood flow by sickled RBCs leads to tissue ischemia, infarction, and pain. Pain crises may involve the bones, chest, abdomen, or any organ, and recurrent vaso-occlusion can result in chronic organ damage. Other complications of vaso-occlusion include stroke, acute chest syndrome, priapism, and splenic infarction.

Sickle cell anemia is an autosomal recessive genetic condition where the beta-globin protein subunit of hemoglobin is misshapen, which ultimately leads to a sickle-shaped red blood cell, which is prematurely destroyed and can get stuck in small blood vessels.[9]

Vascular occlusion, by interrupting blood supply, causes tissue damage, exacerbates ischemia-reperfusion injury, and ultimately leads to damage to limbs and vital organs. In sickle cell patients, vaso-occlusive pain crises are linked to microvascular obstruction by sickled erythrocytes and adhesive blood cell aggregates, leading to ischemia and severe pain. Repeated episodes of vaso-occlusion contribute to cumulative end-organ damage over time.

HbSS is the most common and severe form of disease. It occurs when an individual inherits one sickle cell gene from each parent. CRISPR/Cas9 gene-editing was studied to correct sickle mutation in HBB, creating adequate HbF level to undo sickling.

Mutations in the hemoglobin beta (HBB) gene cause sickle cell anemia. Sickle cell disease is one of the most common monogenic disorders worldwide.

Sickle cell disease is an inherited blood disorder in which the red blood cells contain mostly hemoglobin S. When hemoglobin S loses oxygen, it can polymerize, forming long fibers that distort red blood cells into a sickle shape. These sickled cells are rigid and can obstruct small blood vessels, leading to episodes of pain called vaso-occlusive crises, as well as damage to organs due to reduced blood flow and chronic hemolytic anemia.

Sickle cell anemia is caused by a mutation in the hemoglobin beta gene (HBB) called HbS. Each person inherits two copies of the HBB gene, one from each parent.