Normal Function

The HBB gene provides instructions for making a protein called beta-globin. Beta-globin is a component (subunit) of a larger protein called hemoglobin, which is located inside red blood cells. In adults, hemoglobin consists of four protein subunits: usually two subunits of beta-globin and two subunits of a protein called alpha-globin, which is produced from another gene called HBA. Each of these protein subunits is attached (bound) to an iron-containing molecule called heme; the iron in the center of each heme can bind to one oxygen molecule. Hemoglobin within red blood cells binds to oxygen molecules in the lungs. These cells then travel through the bloodstream and deliver oxygen to tissues throughout the body.

Health Conditions Related to Genetic Changes

Beta thalassemia

Hundreds of variants (also known as mutations) in the HBB gene have been found to cause beta thalassemia. Most of the variants involve a change in a single DNA building block (nucleotide) within or near the HBB gene. Other variants insert or delete a small number of nucleotides in the HBB gene.

HBB gene variants that decrease beta-globin production result in a condition called beta-plus (β+) thalassemia. Variants that prevent cells from producing any beta-globin result in beta-zero (β0) thalassemia.

Problems with the subunits that make up hemoglobin, including low levels of beta-globin, reduce or eliminate the production of this molecule. A lack of hemoglobin disrupts the normal development of red blood cells. A shortage of mature red blood cells can reduce the amount of oxygen that is delivered to tissues to below what is needed to satisfy the body's energy needs. A lack of oxygen in the body's tissues can lead to poor growth, organ damage, and other health problems associated with beta thalassemia.

Methemoglobinemia, beta-globin type

Variants in the HBB gene have been found to cause methemoglobinemia, beta-globin type, which is a condition that alters the hemoglobin within red blood cells. These variants often affect the region of the protein that binds to heme. For hemoglobin to bind to oxygen, the iron within the heme molecule needs to be in a form called ferrous iron (Fe2+). The iron within the heme can change to another form of iron called ferric iron (Fe3+), which cannot bind to oxygen. Hemoglobin that contains ferric iron is known as methemoglobin and is unable to efficiently deliver oxygen to the body's tissues.

In methemoglobinemia, beta-globin type, variants in the HBB gene alter the beta-globin protein and promote the heme iron to change from ferrous to ferric. This altered hemoglobin gives the blood a brown color and causes a bluish appearance of the skin, lips, and nails (cyanosis). The signs and symptoms of methemoglobinemia, beta-globin type are generally limited to cyanosis, which does not cause any health problems. However, in rare cases, severe methemoglobinemia, beta-globin type can cause headaches, weakness, and fatigue.

Sickle cell disease

Sickle cell anemia (also called homozygous sickle cell disease or HbSS disease) is the most common form of sickle cell disease. This form is caused by a particular variant in the HBB gene that results in the production of an abnormal version of beta-globin called hemoglobin S or HbS. In this condition, hemoglobin S replaces both beta-globin subunits in hemoglobin.

The variant that causes hemoglobin S changes a single protein building block (amino acid) in beta-globin. Specifically, the amino acid glutamic acid is replaced with the amino acid valine at position 6 in beta-globin, written as Glu6Val or E6V. Replacing glutamic acid with valine causes the abnormal hemoglobin S subunits to stick together and form long, rigid molecules that bend red blood cells into a sickle (crescent) shape. The sickle-shaped cells die too early, which can lead to a shortage of red blood cells (anemia). The sickle-shaped cells are rigid and can block small blood vessels, causing severe pain and organ damage.

Variants in the HBB gene can also cause other abnormalities in beta-globin, leading to other types of sickle cell disease. These abnormal forms of beta-globin are often designated by letters of the alphabet or sometimes by a name. In these other types of sickle cell disease, just one beta-globin subunit is replaced with hemoglobin S. The other beta-globin subunit is replaced with a different abnormal variant, such as hemoglobin C or hemoglobin E.

In hemoglobin SC (HbSC) disease, the beta-globin subunits are replaced by hemoglobin S and hemoglobin C. Hemoglobin C results when the amino acid lysine replaces the amino acid glutamic acid at position 6 in beta-globin (written Glu6Lys or E6K). The severity of hemoglobin SC disease is variable, but it can be as severe as sickle cell anemia. Hemoglobin E (HbE) is caused when the amino acid glutamic acid is replaced with the amino acid lysine at position 26 in beta-globin (written Glu26Lys or E26K). In some cases, the hemoglobin E variant is present with hemoglobin S. In these cases, a person may have more severe signs and symptoms associated with sickle cell anemia, such as episodes of pain, anemia, and abnormal spleen function.

Other conditions, known as hemoglobin sickle-beta thalassemias (HbSBetaThal), are caused when variants that result in hemoglobin S and beta thalassemia (described above) occur together. Variants that combine sickle cell disease with beta-zero (β0) thalassemia lead to severe disease, while sickle cell disease combined with beta-plus (β+) thalassemia is generally milder.

Other disorders

Hundreds of variations have been identified in the HBB gene. These changes result in the production of different versions of beta-globin. Some of these variations cause no noticeable signs or symptoms and are found when blood work is done for other reasons, while other HBB gene variations may affect a person's health. Two of the most common variants are hemoglobin C and hemoglobin E (described above).

Hemoglobin C (HbC), caused by the Glu6Lys variant in beta-globin, is more common in people of West African descent than in other populations. People who have two hemoglobin C subunits in their hemoglobin, instead of normal beta-globin, have a mild condition called hemoglobin C disease. This condition often causes chronic anemia, in which the red blood cells are broken down prematurely.

Hemoglobin E (HbE), caused by the Glu26Lys variant in beta-globin, is a variant of hemoglobin most commonly found in the Southeast Asian population. When a person has two hemoglobin E subunits in their hemoglobin in place of beta-globin, a mild anemia called hemoglobin E disease can occur. In some cases, the variants that produce hemoglobin E and beta thalassemia (described above) are found together. People with this hemoglobin combination can have signs and symptoms ranging from mild anemia to severe thalassemia major.

Other Names for This Gene

• beta globin
• beta-globin
• HBB_HUMAN
• hemoglobin beta gene
• hemoglobin, beta
• hemoglobin--beta locus

Genomic Location

Signs and symptoms of sickle beta thalassemia may include:

• Anemia (low levels of red blood cells)
• Repeated infections
• Frequent episodes of pain
• Pulmonary hypertension
• Acute chest syndrome (pneumonia-like condition due to entrapment of infection or sickle cells in the lungs)
• Stroke
• Enlarged spleen and/or liver
• Heart murmurs
• Delayed puberty
• Slowed growth
• Jaundice

The symptoms of sickle beta thalassemia vary in severity based on the amount of normal hemoglobin made. Affected people may have no normal hemoglobin (called sickle beta zero thalassemia) or a reduced amount of normal hemoglobin (called sickle beta plus thalassemia). Although these two forms share many of the same features, people with sickle beta zero thalassemia are generally more severely affected than those with sickle beta plus thalassemia. For example, people with sickle beta plus thalassemia generally experience less frequent episodes of pain and are less likely to develop stroke, pulmonary hypertension and acute chest syndrome.

In the United States, babies affected by sickle beta thalassemia are often diagnosed at birth through newborn screening. In the absence of newborn screening, a diagnosis is usually suspected in infants or young children with signs and symptoms associated with the condition. Specialized laboratory tests that measure the amounts of abnormal hemoglobin in the blood and/or genetic testing to identify changes (mutations) in the HBB gene can be used to confirm a diagnosis.

Carrier testing for at-risk relatives and prenatal testing are possible if both disease-causing mutations in the family are known.

Treatment for sickle beta thalassemia is supportive and usually depends on the signs and symptoms present in each person. It is generally recommended that all affected people drink plenty of water; avoid climate extremes, activities that lead to inflammation and extreme fatigue; and stay up-to-date on all immunizations. Because sickle beta thalassemia is associated with a variety of health problems, affected people are usually followed closely by their healthcare provider with regular physical examinations that may include specialized laboratory tests and imaging studies (i.e. chest X-ray, transcranial doppler ultrasound, ECG). Blood transfusions may be prescribed on a regular basis for affected people with a history of or risk factors for stroke and other specific health problems, such as pulmonary hypertension. Hydroxyurea, a drug approved by the U.S. Food and Drug Administration for the treatment of sickle cell disease, can decrease the frequency and severity of pain episodes; reduce the need of blood transfusions; and increase life span.