Hemoglobin variants

April 28, 2022

Human hemoglobin is formed of two pairs of globin chains to each of which is attached one molecule of heme.

Classification of Hemoglobin Variants

On human chromosomes, alpha type genes are located on human chromosomes No. 16 and beta type genes are clustered in human chromosome No.11.

The globin chain genes have introns* between coding sequences which are removed after transcription during mRNA processing. Abnormalities in the primary sequence of globin chains would lead to hemoglobinopathies. Abnormalities in the rate of synthesis of hemoglobin would result in thalassemias.

* Introns are noncoding sections of an RNA transcript, or the DNA encoding it, that are spliced out before the RNA molecule is translated into a protein. The sections of DNA (or RNA) that code for proteins are called exons.

FUNCTION: They serve as hot spots for recombination in the formation of new combinations of exons. In other words, they are in our genes because they have been used during evolution as a faster pathway to assemble new genes.

The hemoglobin variant mostly may be either alpha chain variant or beta chain variant. Although rarely,

gamma and delta chains variants have also been found out.

Normal Hemoglobin types include:

1. Hb A: Hb A is formed of 2 Alpha (α) protein chains and 2 Beta (β) protein chains. It makes up about 95% - 98% of haemoglobin found in adults.

2. Hb A2: Hb A2 is formed of 2 Alpha (α) protein chains and 2 Delta (δ) protein chains. It makes up about 2% - 3% of haemoglobin found in adults.

3. Hb F: Hb A is formed of 2 Alpha (α) protein chains and 2 Gamma (γ) protein chains. It makes up about 1% of hemoglobin found in adults. It is the primary hemoglobin produced by the foetus during pregnancy. Its production usually falls to a low level shortly after birth and reach adults level by 1-2 year.

The alpha (α) chain is common to all three types of Hb molecule.

The alpha (α) chain is directed by two alpha (α) genes, α1 and α2 on chromosome 16,

and

Beta (β) and Delta (δ) chains are directed by single genes on chromosome 11.

The Gamma (γ) chain is directed by two genes Gγ and Aγ, present on chromosome 11.

The four chains are associated in the form of a tetramer. The α1 and β1 contact is the strongest and involves may amino acids with many interlocking sidechains. The binding of heme molecule into a ‘heme pocket’ in each chain is vital for the stability of hemoglobin molecule and its oxygen carrying capacity.

Other hemoglobin variants:

1. Hb Gower 1

It is formed of 2 Zeta (ζ) and to 2 epsilon (ε) and it is found as a minor hb in the early embryo or embryonic life. It is the primarily embyonic hemoglobin. It is relatively upstable breaking down easily. It disappears by the 3rd month of pregnancy in favour of Hb Gower 2.

2. Hb Gower 2

It is formed of 2 alpha (α) and to 2 epsilon (ε) protein chains. It is a formed of hemoglobin existing at low levels during embryonic and fetal life. It is unstable, though not as much as Hb Gower 1. Due to its relative stability compared to hemoglobin Gower 1 and hemoglobin S, it has been proposed as a subject for reactivation in the adult in cases of severe β thalassemia and hemoglobinopathies in subjects for which the reactivation of hemoglobin F is contraindicated due to toxicity concerns.

3. Hb Portland - I

It is formed of 2 Zeta (ζ) and 2 Gamma (γ) protein chains. It is a formed of hemoglobin existing at low levels during embryonic and fetal life.

4. Hb Portland - II

It is formed of 2 Zeta (ζ) and 2 Beta (β) protein chains. It is a formed of hemoglobin existing at low levels during embryonic and fetal life. It is quite unstable, more so than even Hb Gower 1, and breaks down very rapidly under stress. Despite this, it has been also proposed as a candidate for reactivation in cases of severe α thalassemia or hemoglobinopathies afflicting the alpha chains.

5. Hemoglobin C

It is an abnormal type of hemoglobin, the protein in red blood cells that carries oxygen. It is a type of hemoglobinopathy. The disease is caused by a problem with a gene called beta globin.

People with one copy of the gene for hemoglobin C do not experience symptoms, but can pass the abnormal gene on to their children.

Note: Hemoglobin C disease is a blood disorder passed down through families. It leads to a type of anemia, which occurs when red blood cells break down earlier than normal.