Normal Hemoglobin Variants are produced during different development stages depending on the genetic code of a human. Typically, there is Adult Hemoglobin (Hemoglobin A), Fetal Hemoglobin (Hemoglobin F), and Embryonic Hemoglobin (Hemoglobin E). If the person’s DNA fails to provide a proper code to produce the normal Hemoglobin Protein Chains, abnormal chains will be produced leading to constructing abnormal hemoglobin variants that may causes disease. We will speak here about the Normal Hemoglobin Variants. I have spoken previously about the benefits of having different Hemoglobin Variants and I mentioned that different Hemoglobin Variants normally have different functions during the different stages of development. I have also demonstrated how hemoglobin variant differ between each other based on their structure which depends on genetics at the first place. A hemoglobin molecule structure contains protein chains of amino acids. Different chains found in a hemoglobin molecule lead to giving the hemoglobin molecule its own unique biochemical and physical properties that differentiates it from molecules of other hemoglobin variants. If you are not familiar with how human genetics affect the structure of a hemoglobin molecule, I suggest you to read about “Genetics and structure of Hemoglobin Variants”.
Hemoglobin Levels Normal Hemoglobin Levels Normal Alternations to Hemoglobin Levels Causes of Low Hemoglobin Levels Causes of High Hemoglobin Levels Hemoglobin Variants Benefits of having different Hemoglobin Variants Genetics and structure of Hemoglobin Variants Normal Hemoglobin Variants Embryonic Hemoglobin Hemoglobin Gower 1 Hemoglobin Gower 2 Hemoglobin Portland 1 Hemoglobin Portland 2 Fetal Hemoglobin (Hemoglobin F) Hemoglobin F Normal Levels Function of Hemoglobin F Adult Hemoglobin (Hemoglobin A) Hemoglobin A1 Hemoglobin A2
Embryonic Hemoglobin (Hemoglobin ε)
Embryonic Hemoglobin is commonly known as Hemoglobin Epsilon or Hemoglobin ε. Embryonic Hemoglobin is the hemoglobin type found in a human embryo. When an ovum is finalized, the very first cell of a human is found, that cell is called a Zygote. After 30 hours of fertilization, the Zygote starts a long process of division to create larger number of cells known all together as Blastocyst. Even though the blastocyst has the same size of a zygote, its multiple cell help it to attache and implant into the Uterine Wall of the mother. The embryonic period of human begins when the blastocyst is completely implanted (approximately by the end of second week after fertilization) and ends approximately at the eighth week after fertilization.
Human body membranes are not found at the early stages of development. In other words, heart, brain, bone structure, liver, spleen and all other member are not found at the very first weeks after fertilization. Blood and blood vessels are not found at those early weeks, blood starts to appear as a group of unconnected spots known as Blood Islands. Blood is produced by the Yolk Sac at this early stage. The blood islands later expand and connect together to form an elementary network of blood vessels.
Studies suggest that Embryonic Hemoglobin can bind with Oxygen as well as Fetal and Adult Hemoglobin can do. However, unlike Fetal and Adult Hemoglobin, the properties and function of Embryonic Hemoglobin are still not highly defined. During the Embryonic Period, nutrition is provided in the form of yolk. In other words, blood is not what mainly transports nutrition to the body cells as it does later.
When a biological container is developed, it is not developed empty and filled later with its contents. Instead, a container in biology is usually developed with its contents. For this reason, I believe that blood vessels are created along with the embryonic blood as a foundation for functioning circulatory system at later stages.
Vitelline Circulation is a blood circulation that occurs between the Yolk Sac and the heart tubes of an embryo. It is believed that the blood carries nutrition from the yolk sac to rest of the embryo the same way blood does for fetus and adults. Also blood cells are produced in the yolk sac at this early stage and it is believed a supply of newly produced blood cells is taken from the yolk sac during this circulation.
Embryonic Hemoglobin is unstable and it breaks down easily. It also remains for a very short period of time and in a very low amounts that makes it difficult to study it as extensively as Fetal Hemoglobin and Adult Hemoglobin are studied. Like all types of hemoglobin variants, Embryonic Hemoglobin is also a tetramer ( a protein that its molecule is built up from four protein subunits). There are four types of Embryonic Hemoglobin or Hemoglobin Epsilon:
Hemoglobin Gower 1 is referred to as Fully Embryonic Hemoglobin because its molecule contains two Zeta (ζ) subunit chains and tow Epsilon (ε) subunit chains which are produced only during the embryonic period and not found normally in either Adult or Fetal Hemoglobin.
Zeta (ζ) subunit is an α-like hemoglobin subunit, which means it normally binds with Beta-like hemoglobin subunits in order to make up a hemoglobin molecule. The genetic coding for Zeta subunit is found in Chromosome 16 which also contains the genetic code for all Alpha-like hemoglobin subunits. Zeta subunit and the other alpha-like subunits belong to the same gene cluster known as Alpha-globin.
Epsilon (ε) subunit on the other hand, is a β-like hemoglobin subunit and it normally binds with Alpha-like hemoglobin subunits to make up a hemoglobin molecule. The genetic code for Epsilon is found in Chromosome 11 which is the some chromosome where the genetic code for all Beta-Like subunits is found. The Zeta chain genetic code is found along with the genetic code for other beta-like subunits in the 45 kb genetic cluster.
Both of Zeta chains and Epsilon chains are produced in the Yolk Sac only during the embryonic period. They both may be found in fetus after the eighth week, but their levels decease dramatically until their level be less than %1 at the 16th to the 25th weeks in a chromosomally normal fetus. In an abnormal fetus, it my take additional three to six weeks for Zeta and Epsilon subunits to be less than %1.
Hemoglobin Gower 1 has the biochemical code ζ2 ε2 because its molecular structure contains two Zeta chains and two Epsilon chains. It is also known as HbE Gower-1. Hemoglobin Gower 1 is also the primary type of embryonic hemoglobin and it is found in very levels during the embryonic period. However, Hemoglobin Gower 1 is highly unstable and it breaks down very quickly and doesn’t normally found in fetus after the embryonic period.
Hemoglobin Gower 2 or HbE Gower-2 is a Semi-Embryonic Hemoglobin because its molecule is made up of two Alpha (α) hemoglobin subunits and two Epslon (ε) hemoglobin subunits. While Epslon protein chains are synthesized in the Yolk Sac during the Embryonic Period only, Alpha protein chains are produced after the embryonic period in both fetus and adult. For this reason, half of protein chins in Hemoglobin Gower 2 molecules are embryonic subunits and the other half are not embryonic subunits. And this is where the name Semi-Embryonic Hemoglobin comes from.
Hemoglobin Gower 2 if found in the embryonic blood in low levels compared to Hemoglobin Gower 1 which is the primary embryonic hemoglobin variant. Also, in comparison to Hemoglobin Gower 1, Hemoglobin Gower 2 is more stable and it can stay in blood for longer time. HbE Gower-2 normally found in low levels in fetal blood and it can stay for few weeks after the end of embryonic period.
Hemoglobin Gower 2 molecular structure is α2 ε2 and it may be used to treat condition of abnormal hemoglobin molecular structure as suggested by promising results from studying its effect on mice. Later, we will learn more about using normal hemoglobin variants to treat hemoglobin related conditions.
Hemoglobin Portland 1 (a.k.a.HbE Portland-1) is another Semi-Embryonic Hemoglobin variant. Hemoglobin Portland 1 molecule contains two Zeta (ζ) subunits and two Gamma (γ) subunits. While Zeta subunits are mainly found in embryonic hemoglobin, Gamma subunits are mainly found in fetal hemoglobin (Hemoglobin F). Hemoglobin Portland 1 is semi-embryonic because it has both embryonic and fetal subunits.
Hemoglobin Portland 1is also unstable and it is found in low levels in embryo blood. Hemoglobin Portland 1 has the molecular structure code ζ2 γ2.
Hemoglobin Portland 2 is also known as HbE Portland-2is also a Semi-Embryonic Hemoglobin variant. Hemoglobin Portland 2 has a molecular structure that includes both of the embryonic Zeta (ζ) subunits and the adult Beta (β) and it has the molecular structure of ζ2 β2. Hemoglobin Portland 2 is very unstable and it doesn’t stay in fetus body for long time after the embryonic period.
Studies on mice has suggested the possibility of reactivating Hemoglobin Portland 2 in adults to treat some hemoglobin related condition. We will learn about reactivating embryonic hemoglobin and fetal hemoglobin later on.
Fetal Hemoglobin or Hemoglobin F (HbF)is the primary hemoglobin variant found in fetus. Fetal Hemoglobin molecules are made up of two Alpha (α) hemoglobin subunits and two Gamma (γ) subunits, the molecular code for Hemoglobin F is α2γ2 .
Hemoglobin F is normally found in adults in addition to be found in fetus. But, unlike fetus, Hemoglobin F is normally found in adults at very low levels.
Embryonic blood normally contains Alpha units and Gamma subunits, which Hemoglobin F molecules are built up from. However, Hemoglobin F itself is not normally found during the in embryonic blood. In embryonic blood, both Alpha subunits and Gamma subunits bind only with Epsilon subunits and Zeta subunits respectively to create semi-embryonic hemoglobin molecules. Alpha subunits and Gamma subunits don’t bind together to create hemoglobin F molecules during the embryonic period.
After birth, a newborn body stops producing Hemoglobin F and starts producing Adults Hemoglobin (Hemoglobin A). The hemoglobin F ratios in blood start to decrease dramatically to less than %1 as the human body grows and produces more Hemoglobin A. Hemoglobin F is not ceased to exist in adult blood because Red Blood Cells that contain hemoglobin F continue to divide even after the body stops producing it. The following is a listing of Hemoglobin F normal levels:
- Newborn: 50% to 80%
- Infants less than 6 months of age: less than 8%
- Infants and Children over 6 months of age: 1% to 2%
- Adults: 0.8% to 2%
Hemoglobin F is found to enable gas and nutrition transfer from the maternal blood which has Hemoglobin A to the fetal blood which has hemoglobin B. When I talked about the benefits of having different hemoglobin variants, I have explained why maternal blood shouldn’t mix fetal blood or circulate in the the fetus body.
I have also given and example of Oxygen transfer from Adult Hemoglobin (Hemoglobin A) to the Fetal hemoglobin (Hemoglobin F). I have mentioned that Fetal Hemoglobin has a lower Oxygen partial pressure than the Oxygen partial pressure of Adult Hemoglobin which causes Oxygen to move from the mother’s red blood cells to the fetus without having any direct contact between the maternal blood and the fetal blood.
Hemoglobin F Role in Treating Abnormal Hemoglobin Mutations
Fetal Hemoglobin production stops after birth by stopping the production of Gamma (γ) subunits which unite with Alpha (α) subunits to produce Hemoglobin F molecules. Instead of producing Gamma subunits, the newborn body produces more quantities of Beta (β) subunits which which unite with Alpha subunits to produce molecules of Adult Hemoglobin.
Unfortunately, due to some Hemoglobin related genetic disorders the newborn body may fail in producing normal Beta subunit and and produces abnormal Beta subunits that cause abnormal hemoglobin molecules to be produced which in some conditions may defect the shape or the function of the Red Blood Cell itself.
Hemoglobin related genetic disorders that cause the production of defective hemoglobin subunits are called Hemoglobinopathies. One of the successful methods that treat Hemoglobinopathies is to reverse what happens after birth and reactivate the production of Fetal Hemoglobin once again. By producing Hemoglobin F once again, Hemoglobin F levels will increase in the adult blood leading to performing normal hemoglobin functionality and decreasing the symptoms of Hemoglobinophathies.
Hemoglobinopathies treatment by inducing Hemoglobin F usually succeed with most of the patients. However, some patient may show symptoms of toxicity. For this reason drugs that are used to induce Hemoglobin F are given in low doses with a careful watch on patient reaction before increasing the dosage.
When I spoke about Embryonic Hemoglobin, I have talked about studies on mice that have suggested inducing Hemoglobin Gower 2 and Hemoglobin Portland 2 instead of inducing Hemoglobin F to treat Hemoglobinopathies in order to avoid possible toxicity. We will learn more about Hemoglobinopathies and Hemoglobin F induction in later discussions.
Adult Hemoglobin or Hemoglobin A (HbA) is the primary hemoglobin variant found in Adults. As Hemoglobin F levels decrease after birth, Hemoglobin A becomes the predominant hemoglobin variant in human blood and Hemoglobin A levels increase up to %98 in adults.
Hemoglobin A molecules contain two Alpha (α) subunits and two Beta (β) subunits. Hemoglobin A has the molecular code α2β2. Most of condition related abnormal Hemoglobin Variants are found when the human body produces defective mutations of Hemoglobin A.
The normal function of hemoglobin in to bind with (hold on to) the molecules of Oxygen, Carbon Dioxide, and other ligands in order for the Red Blood Cells to deliver them to and take them from the different body organs. Hemoglobin molecules bind with ligands, the electric charges of their ions will change and the coil like shape of the hemoglobin subunits will alter as well. Depending on the kind of the ligand, the hemoglobin molecule will have new unique chemical and physical characteristics that can be used to identify what is the hemoglobin molecule is binding with. For example a hemoglobin molecule that binds with Oxygen will have different characteristics from another hemoglobin molecule that binds with glucose.
Hemoglobin A1, or simply Hemoglobin A1 (HbA1)is that form of Hemoglobin A which binds strongly with glucose. The strong bond between Hemoglobin A1 and glucose will make it difficult to separate glucose from Hemoglobin A1 molecules once the bond is established. For this reason Hemoglobin A1 is some times referred to as Gycated Hemoglobin.
Due to the strong bond between Hemoglobin A1 and glucose, the glucose ligand will remain attached to the Red Blood Cell of Hemoglobin A1 for the rest of the Red Blood Cell lifetime and more Hemoglobin A1 molecules will accumulate within the the same Red Blood Cells as long as there is glucose to bind with them which leads to increase the level of Hemoglobin A1 in the blood.
Normally, 7% of Hemoglobin A is Hemoglobin A1. When excessive amounts of sugar are consumed over a long period of time, more Hemoglobin A1 accumulate on the Red Blood Cells, which makes Hemoglobin A1a very suitable marker to monitor the levels of plasma glucose over a long period of time. However, there are three types of Hemoglobin A1, Hemoglobin A1a (HbA1a), Hemoglobin A1b (HbA1b), and Hemoglobin A1c (HbA1C).
All the three types of Hemoglobin A1 bind strongly with glucose. However, HbA1a, and HbA1b tend to bind with glucose in lower ratios compared to HbA1c. As a result, monitoring HbA1c levels instead of monitoring Hemoglobin A1 will provide physicians with a more accurate picture of the patient’s diabetic control. The term Glycated Hemoglobin is also more used to refer to Hemoglobin A1c than it is used with Hemoglobin A1.
Hemoglobin A2 or Hemoglobin A2 (HbA2) is a hemoglobin variant that is normally found in low levels in adults’ blood. Hemoglobin A2 molecules contain tow Alpha (α) hemoglobin subunits and two Delta (δ) hemoglobin subunits. Delta subunits are Beta-like hemoglobin subunits. Similar to any other Beta-like subunits, the genetic code for Delta subunits is found in the Beta-globin genetic group of Chromosome 11.
The normal level of Hemoglobin A2 is between 1.5% and 3% in adults. The molecular structure code for Hemoglobin A2 is α2δ2.
The Normal Hemoglobin Variants and Subunits figure will give you a very good idea about how Alpha-like and Beta-like subunits bind together to create a normal hemoglobin variant molecule. As you notice, two of each subunit from the Alpha-like side bind with two of each subunit from the Beta-like side to create a molecule of a normal hemoglobin variant. Only Zeta(ζ) and Delta (δ) subunits don’t bind together to create a normal hemoglobin variant.
At the end, we have the seven normal hemoglobin variants we have demonstrated earlier.