HBB: The Gene Associated with Sickle Cell Anemia
Official Gene Symbol: HBB Name of Gene Product: hemoglobin, beta Alternate Name of Gene Product: beta globin Locus: 11p15.5 - The HBB gene is found in region 15.5 on the short (p) arm of human chromosome 11. Gene Structure: The normal allelic variant for this gene is 1600 base pairs (bp) long and contains three exons. mRNA: The intron-free mRNA transcript for the HBB gene is 626 base pairs long. See the NCBI sequence record NM_000518 to access the mRNA sequence data. Coding Sequence (CDS): 444 base pairs within the mRNA code for the amino acid sequence of the gene's protein product. Protein Size: The HBB protein is 146 amino acids long and has a molecular weight of 15,867 Da. See the annotated HBB protein sequence record in Swiss-Prot. Protein Function: Hemoglobin molecules, which reside in red blood cells, are responsible for carrying oxygen from the lungs to various parts of the body for use in respiration. The HBB gene codes for one of the two types of polypeptide chains found in adult hemoglobin. Normal adult hemoglobin is a tetrameric protein consisting of two alpha chains and two beta chains. HBB codes for the beta chain, which is often referred to as beta globin. Mutant beta globin is responsible for the sickling of red blood cells seen in sickle cell anemia. Protein Structure The structure of normal deoxy hemoglobin is shown in Figure 1. The four gray clusters are noncovalently bonded heme groups. Each heme serves as a contact site for binding one molecule of oxygen. The two gold spheres near the top of the molecule are phosphate groups. The green and blue chains are alpha chains, and the gold and aqua chains are beta chains. The red box highlights the general region of two beta chains where the sixth glutamic acid residue is located. A genetic variant associated with this amino acid is the most common cause of sickle cell anemia. Figure 2 shows the clumping together of two deoxy hemoglobin molecules that contain this genetic variant.
Common Disease Causing Mutation
Although several hundred HBB gene variants are known, sickle cell anemia is most commonly caused by the hemoglobin variant Hb S. In this variant, the hydrophobic amino acid valine takes the place of hydrophilic glutamic acid at the sixth amino acid position of the HBB polypeptide chain. This substitution creates a hydrophobic spot on the outside of the protein structure that sticks to the hydrophobic region of an adjacent hemoglobin molecule's beta chain. This clumping together (polymerization) of Hb S molecules into rigid fibers causes the "sickling" of red blood cells. Polymerization occurs only after red blood cells have released the oxygen molecules that they carry to various tissues throughout the body. Once red blood cells return to the lungs where hemoglobin can bind oxygen, the long fibers of Hb S molecules depolymerize or break apart into single molecules. Cycling between polymerization and depolymerization causes red blood cell membranes to become rigid. The rigidity of these red blood cells and their distorted shape when they are not carrying oxygen can result in blockage of small blood vessels. This blockage can cause episodes of pain and can damage organs. Sickle cell anemia is an autosomal recessive genetic disorder. For the disease to be expressed, a person must inherit either two copies of Hb S variant or one copy of Hb S and one copy of another variant. Carriers, who have one copy of the normal HBB gene (Hb A) and one copy of Hb S, are described as having sickle cell trait and do not express disease symptoms. To learn more about sickle cell anemia, see the Disease Profile. Additional Resources HBB Records from Different Bioinformatics Databases
References Johns Hopkins University,
Baltimore, MD. Online Mendelian Inheritance in Man, OMIM (TM).
MIM No.141900. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM>
(September 2003). Joint Center for
Sickle Cell and Thalassemic Disorders. "How Does Sickle Cell Cause Disease?"
<http://sickle.bwh.harvard.edu/scd_background.html>
(September 2003). |
Last modified: September 12, 2003
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