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More information on haemoglobin and disease

Haemoglobin is a protein that is carried by red blood cells. Its main function is to pick up oxygen in the lungs and deliver it to the peripheral tissues to maintain the viability of cells. Haemoglobin is made from two similar proteins, usually referred to as subunits, which “stick together”. Both subunits must be present for the haemoglobin to function normally. One of the subunits is called alpha, and the other is beta. Inside each subunit, there is a small iron-containing molecule called heme, to which oxygen is bound. Before birth, the beta protein is not expressed. Instead, a chain called gamma is produced.

Like all proteins, the “instructions” to synthesise haemoglobin are found in DNA (the material that makes up genes). Normally, an individual has four genes that code for the alpha protein, or alpha chain. Two other genes code for the beta chain. The alpha chain and the beta chain are made in precisely equal amounts, despite the differing number of genes. The protein chains join in developing red blood cells, and remain together for the life of the red cell.

The composition of haemoglobin is the same in all people. The genes that code for haemoglobin are identical throughout the world. Occasionally, however, one of the genes has a change or variant. Although the changes that produce abnormal haemoglobins are rare, several hundred haemoglobins variants exist. Most variant haemoglobins function normally, and are only found through specialized research techniques. Some haemoglobin variants, however, do not function normally and can produce clinical disorders, such as sickle cell disease.

Usual types of haemoglobin:

Haemoglobin A: This is the designation for the most common haemoglobin variant that exists after birth. Haemoglobin A is a tetramer with two alpha chains and two beta chains (a2b2).

Haemoglobin A2: This is a minor component of haemoglobin found in red cells and consists of two alpha chains and two delta chains (a2d2). Haemoglobin A2 generally comprises less that 3% of the total red cell haemoglobin.

Haemoglobin F: Haemoglobin F is the predominant haemoglobin during foetal development. The molecule is a tetramer of two alpha chains and two gamma chains (a2g2).

Clinically significant haemoglobin variants

Haemoglobin S: This is the predominant variant in people with sickle cell disease. The disease-causing gene change is found in the beta chain. The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, tribal regions of India and the Middle-East. The carrier frequency ranges between 10% and 25% across equatorial Africa.

Haemoglobin C: Haemoglobin C results from a gene change in beta globin. It can cause sickle cell disease when it is inherited with haemoglobin S. It can also cause haemoglobin C disease when two haemoglobin C variants are inherited. Haemoglobin C is most prevalent in Western Africa, especially in Nigeria and Benin.

Haemoglobin E: This variant results from a gene change in the haemoglobin beta chain. It can cause thalassaemia major or intermedia hen coinherited with beta thalassaemia. Haemoglobin E is extremely common in Southeastern Asia (Thailand, Myanmar, Cambodia, Laos, Vietnam, and India) where its prevalence can reach 30-40%.

Haemoglobin D: There are different types of haemoglobin D variants, but the most vlinically significant is haemoglobin DPunjab (also called DLos Angeles). It results from a gene change in the beta globin chain. It can cause sickle cell disease if coinherited with haemoglobin S. As the name indicated, it is most frequent in the Punjab Area (Northwestern India), where the carrier frequency can be around 2%.

Haemoglobin OArab: This variant results from a gene change in the beta globin chain. It can cause sickle cell disease when it is inherited with haemoglobin S. It is more frequent in North Africa, Middle East and Eastern Europe.

Haemoglobin Lepore: Haemoglobin Lepore is an unusual variant that is th product of the fusion of the beta and delta globin genes. It can cause thalassaemia major/intermedia when a person inherits two copies of haemoglobin Lepore, or when it is inherited with beta thalassaemia. It can also cause sickle cell disease when inherited with haemoglobin S. It occurs most frequently in patients originating from the Mediterranean region.

Last Updated: 20 April 2021