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
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.More About This Health Condition
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.More About This Health Condition
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.More About This Health Condition
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
- hemoglobin beta gene
- hemoglobin, beta
- hemoglobin--beta locus
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review. Am J Epidemiol. 2000 May 1;151(9):839-45. doi: 10.1093/oxfordjournals.aje.a010288. Citation on PubMed
- Bellelli A, Brunori M, Miele AE, Panetta G, Vallone B. The allosteric properties of hemoglobin: insights from natural and site directed mutants. Curr Protein Pept Sci. 2006 Feb;7(1):17-45. doi: 10.2174/138920306775474121. Citation on PubMed
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- Flatz G, Sanguansermsri T, Sengchanh S, Horst D, Horst J. The 'hot-spot' of Hb E [beta26(B8)Glu-->Lys] in Southeast Asia: beta-globin anomalies in the Lao Theung population of southern Laos. Hemoglobin. 2004 Aug;28(3):197-204. doi: 10.1081/hem-120040334. Citation on PubMed
- Fu XH, Liu DP, Liang CC. Chromatin structure and transcriptional regulation of the beta-globin locus. Exp Cell Res. 2002 Aug 1;278(1):1-11. doi: 10.1006/excr.2002.5555. Citation on PubMed
- Mahajan MC, Weissman SM. Multi-protein complexes at the beta-globin locus. Brief Funct Genomic Proteomic. 2006 Mar;5(1):62-5. doi: 10.1093/bfgp/ell001. Epub 2006 Feb 22. Citation on PubMed
- Nagel RL, Steinberg MH. Role of epistatic (modifier) genes in the modulation of the phenotypic diversity of sickle cell anemia. Pediatr Pathol Mol Med. 2001 Mar-Apr;20(2):123-36. Citation on PubMed
- Panigrahi I, Agarwal S. Genetic determinants of phenotype in beta-thalassemia. Hematology. 2008 Aug;13(4):247-52. doi: 10.1179/102453308X316031. Citation on PubMed
- Park KW. Sickle cell disease and other hemoglobinopathies. Int Anesthesiol Clin. 2004 Summer;42(3):77-93. doi: 10.1097/00004311-200404230-00008. No abstract available. Citation on PubMed
- Sadelain M, Rivella S, Lisowski L, Samakoglu S, Riviere I. Globin gene transfer for treatment of the beta-thalassemias and sickle cell disease. Best Pract Res Clin Haematol. 2004 Sep;17(3):517-34. doi: 10.1016/j.beha.2004.08.002. Citation on PubMed
- Schechter AN. Hemoglobin research and the origins of molecular medicine. Blood. 2008 Nov 15;112(10):3927-38. doi: 10.1182/blood-2008-04-078188. Citation on PubMed or Free article on PubMed Central
- Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004 Oct 9-15;364(9442):1343-60. doi: 10.1016/S0140-6736(04)17192-4. Citation on PubMed
- Thein SL. Genetic insights into the clinical diversity of beta thalassaemia. Br J Haematol. 2004 Feb;124(3):264-74. doi: 10.1046/j.1365-2141.2003.04769.x. No abstract available. Citation on PubMed
- Thom CS, Dickson CF, Gell DA, Weiss MJ. Hemoglobin variants: biochemical properties and clinical correlates. Cold Spring Harb Perspect Med. 2013 Mar 1;3(3):a011858. doi: 10.1101/cshperspect.a011858. Citation on PubMed or Free article on PubMed Central