HBA1 and α-thalassemia

This page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.

About α-thalassemia
α-thalassemia is an inherited disease of the blood, caused by the production of abnormal hemoglobin. This reduces the ability of hemoglobin to transport oxygen through the bloodstream.  Though the severity of the disease varies, affected patients typically experience microcytic hypochromic anemia, in which blood cells are unusually small and pale in color.  They usually also suffer from hemolytic anemia, which causes the patients' blood cells to be destroyed by their body.  This leads to swelling of the spleen and liver. [2]  Symptoms of α-thalassemia usually become apparent in infancy or early childhood.   Many patients are relatively unaffected by the disease and may not require treatment [2], but some patients who experience more severe effects of the disease may require frequent blood transfusions [3].

The Gene

Picture
Cluster of α-globin genes on chromosome 16. α1 = HBA1. [2]
The HBA1 gene is located in a cluster of globin genes on chromosome 16.  It encodes α1-globin, a subunit of hemoglobin.  The α-globin genes are duplicated, with HBA2 encoding the α2-globin subunit. 
Upstream of the α-globin genes lies HS-40, a DNA binding region that regulates the expression of HBA1 and HBA2.  Deletions of this region may cause α-thalassemia symptoms in patients with both HBA genes intact. [2]

Effects on Hemoglobin

Picture
Normal hemoglobin molecule (hemoglobin A), showing two α and two β chains. [4]
A normal, diploid non-carrier of thalassemia has four normal copies of the α-globin genes (their genotype is αα/αα).  They produce normal hemoglobin, which has two α and two β chains.  This type of hemoglobin molecule is known as hemoglobin A, or HbA. The HBB gene on chromosome 11 encodes the β-globin chains. [2]

Most cases of α-thalassemia are caused by the deletions of one of the α-globin genes [3].  An individual with one deleted gene copy (-α/αα) is a silent carrier.  These individuals show no symptoms, and their three normal α-globin gene copies are sufficient to synthesize normal hemoglobin.  Individuals with two deleted α-globin genes (--/αα or -α/-α) are said to have the α-thalassemia trait.  They have normal levels of hemoglobin A, but may show mild thalassemia symptoms. [3]
When three of the α-globin genes are deleted (--/-α), the patient experiences full symptoms of α-thalassemia.  Although normal HbA is produced, two less stable forms of hemoglobin are also present.  Hemoglobin H (HbH) is composed entirely of four β-globin chains, and does not transfer oxygen to the tissues as well as HbA.  As a result of the high HbH content in the blood, symptomatic α-thalassemia is known as Hemoglobin H disease.  The second form of unstable hemoglobin is known as hemoglobin Bart (Hb Bart), which has four unusual γ-globin chains that bind oxygen extremely tightly. [2]

Upon deletion of all four α-globin genes (--/--), Hemoglobin Bart syndrome occurs.  The condition is usually diagnosed in a developing fetus.  The only hemoglobin present in the fetus is Hb Bart, which is insufficient to oxygenate the body.  This results in severe edema in the fetus known as hydrops fetalis.  Infants with hydrops fetalis are usually stillborn or die very shortly after birth. [2]

One Family's Struggle with Thalassemia

References
1. Banner photo, Wellcome Images.
2. Alpha-Thalassemia. GeneReviews [Internet]. Galanello, R., Cao, A. Seattle (WA): University of Washington, Seattle; 1993-. 2005 Nov 01 [last           updated 2008 July 15]. (NCBI Bookshelf)
3.
Genes and Disease: ThalassemiaGenes and Disease [Internet]. National Center for Biotechnology Information (US). Bethesda (MD): National       Center for Biotechnology Information (US); 1998-.
4.  The Internet Encyclopedia of Science

Colleen Hannon
Last Updated 5/12/2011
Genetics 677