HBB: The Gene Associated with Sickle Cell Anemia

Approximate gene location is based on Chromosome 11 map from NCBI Entrez Map Viewer.

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.

Figure 1: The Crystal Structure of Human Deoxy- haemoglobin at 1.74 A  Resolution. Source: PDB ID 4HHB as viewed in Protein Explorer	Figure 2: The structure above is a model of two Hb S hemoglobin molecules clumping together. Source: PDB ID 2HBS as viewed in Protein Explorer

Common Disease Causing Mutation

Figure 3: Normal and mutated HBB sequences

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

OMIM Entry for HBB (MIM No 141900)

OMIM Entry for Sickle Cell Anemia (MIM No 603903)

NCBI LocusLink Entry for HBB

GeneCard for HBB

GENATLAS - To access the HBB record enter HBB into the "Symbol Name" search box and click "find" to submit your search.

HBB Nucleotide Sequence

NCBI mRNA Reference Sequence (RefSeq Record NM_000518)

NCBI Genomic Nucleotide Reference Sequence (RefSeq Record NG_000007)

HBB Protein Sequence

HBB_HUMAN - Annotated protein sequence record from Swiss-Prot that provides descriptions of the protein's domains, amino acid sequence variations, secondary structure, and more.

NCBI Protein Reference Sequence (NP_000509)

HBB Protein Structure

4HHB - Protein Data Bank entry for the Crystal Structure of Human Deoxyhemoglobin

2HBS - Protein Data Bank entry for the Crystal Structure of Human Deoxyhemoglobin S (Hb S, the most common mutated form of hemoglobin that causes sickle cell anemia)

HBB Mutation Resources

Human Gene Mutation Database Entry for HBB

HbVar - Database of Human Hemoglobin Variants and Thalassemias

Other HBB Web resources

Hemoglobin - To access a tutorial on normal and sickle cell hemoglobin structures, click on the large "Hemoglobin" link on the Web page created by Dr. Eric Martz at the Department of Microbiology, University of Massachusetts. To access the tutorial, you must be using Netscape Navigator 3.1 or later, and the plug-in Chime should already be installed.

Globin Gene Server - This Web site, developed by the laboratories of Computer Science & Engineering and Biochemistry & Molecular Biology at Pennsylvania State University, provides resources for studying the DNA sequences of genes associated with hemoglobin production.

Research on Sickle Cell Hemoglobin - Take a tour or watch films that examine the structure of fibers created by clumping of Hb S molecules. This resource is provided by the Laboratory of Electron Microscopy, University of Chicago.

Linus Pauling - One of the many achievements of this Nobel-prize winning physical chemist was his discovery that sickle cell anemia is caused by an alteration in the hemoglobin protein's molecular structure. The paper reporting this discovery, "Sickle Cell Anemia, a Molecular Disease," was published in Science in 1949.

Vernon Ingram - Learn more about the scientist who discovered the amino acid substitution that causes sickle hemoglobin.

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).

A. Ashley-Koch, Q. Yang, and R. S. Olney. 1998."Hemoglobin S Allele and Sickle Cell Disease." American Journal of Epidemiology 151 (9): 839-45. <http://www.cdc.gov/genomics/hugenet/reviews/sickle.htm> (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).