Genetics of the Haemoglobins | Human Genetics

In this article we will discuss about the normal and abnormal haemoglobins.

I. Normal Haemoglobin:

Haemoglobin consists of 4 polypeptide (globin) chains each associated with a single haem group. There are 5-6 types of haemoglobins normally present at different stages of life, from zygote to adulthood.

The embryonal haemoglobins (HbE) are heterogeneous and designated Gower-1, Gower-2 and Portland. In the fetal stages fetal haemoglobin (HbF) is present. After birth and in adult life the amount of HbF falls to less than 1 %. In adult stages 90% of the haemoglobin consists of HbA and about 2 % HbA2.

Out of the four globin chains constituting haemoglobin, two known as alpha (α) chains consist of 141 amino acids each and are identical in all types of haemoglobin. The other two chains are different in each type of haemoglobin. Thus HbE with two epsilon chains is written as α2ε2, HbF with two gamma chains as α2γ2, HbA as α2β2 and HbA2 as α2δ2. The β chains each have 146 amino acids but they are structurally different.

Each polypeptide chain is coded for by a different structural gene. The gene loci for the two α chains are on chromosome 16, and for β, γ, δ and e chains on chromosome 11. The genes for the globin chains β and δ in adult humans contain intervening sequences.

II. Abnormal Haemoglobins:

The defects in the globin chains can be divided into the following groups:

(a) The thalassaemias caused by reduction in globin chain synthesis;

(b) Sickle anaemia and other structural variants in globin chains;

(c) Hereditary persistence of fetal haemoglobin (HPFH).

(a) The Thalassaemias:

These are characterised by reduced synthesis of either the α or β chains, likewise designated as α- or β-thalassaemias. The first genetic disorder of this kind was described by Cooley in β-thalassaemia (also called Cooley’s anemia or thalassaemia major). The reduced synthesis of β chains leads to accumulation of α chains which cause damage to the precursors of red blood cells in the bone marrow.

Persons homozygous for the β thalassaemia gene suffer from severe haemolytic anaemia and usually die before puberty. Heterozygous persons are also not normal, but show the defect in a less severe form (thalassaemia minor).

Thalassaemia is of three types depending upon whether there is reduced or absent synthesis of one or more globin chains. Accordingly, there is α-thalassaemia, β-thalassaemia, and 8-3 thalassaemia.

In complete absence of synthesis of a particular globin chain, the thalassaemias are referred to as α⁰, β⁰, and δ-β⁰, respectively. When there is only reduction in globin chain synthesis, the conditions are designated α⁺, β⁺ and δ-β⁺ thalassaemia respectively.

Thalassaemia is a heterogeneous disorder and patients present with a variety of clinical features. The disease is usually inherited as a recessive trait. Clinical presentations range from asymptomatic hypochromic microcytosis to severe anaemia which could be fatal in utero or early childhood.

The heterogeneity may be attributed to several interrelated factors which modulate the globin genes, such as elevated synthesis of fetal globin subunits, and inheritance of other structural haemoglobin variants like HbS, HbD, HbE and others. Some individuals may inherit more than one effective globin chain gene.

Thalassaemia seems to result from the collective consequences of inadequate haemoglobin concentration and accumulation of unbalanced globin subunits, which leads to haemolytic anaemia and inefficient erythropoiesis.

α-Thalassaemia:

Among the 4 α loci in humans, one or more loci may be non-functional.

Thus there are four kinds of thalassaemias:

(1) α-thal-2 trait; only one of the four A-globin gene loci is non-functional. The individual may not express the trait but is a silent carrier.

(2) α-thal-1 trait; two of the four A-globin gene loci are non-functional.

(3) HbH disease in which three loci do not function.

(4) Hydrops faetalis with Hb Barts in which all four loci are defective. This condition is not compatible with life.

Most of these conditions are due to deletions of the α-globin genes; some non-deletional forms of α-thalassaemia have also been described. Haemoglobins that are structurally abnormal have been associated with α-thalassaemia.

β-Thalassaemia:

Mutation in the single β -globin gene on chromosome 11 results in reduced synthesis of β-globin chains, giving rise to β-thalassaemia. More than 100 point mutations have been detected in the β- globin gene. The condition in homozygous patients is called Cooley’s anaemia or thalassaemia major, is severe and the patient is dependent on transfusion.

The nature of the mutation determines severity of homozygotes, so that β° patients (complete absence of β chain synthesis) are severely affected as compared to β⁺ patients (reduced synthesis of β chain).

The various forms of P-thalassaemias have been correlated with several different mutations that could affect multiple steps in the pathway of globin gene expression, namely, transcription, processing of the precursor of mRNA, translation, and post-translational stability of the β-globin chain.

Among these, 12 transcription mutations, some RNA modification mutants, as well as some RNA cleavage and polyadenylation (mutations in poly A tail) mutants have been described which produce a mild form of β⁺-thalassaemia. The RNA splicing mutants result in blocking functional activity of mRNA, and as expected there is no chain synthesis, leading to β⁰-thalassaemia.

The same happens in the case of translation mutants for which 37 mutations have been found resulting in non-functional mRNA and absence of polypeptide chains. The mis-sense mutants produce highly unstable β-globin chains which are degraded rapidly after synthesis.

(b) Sickle Haemoglobin:

Structural variations in α or β globin chains are due to amino acid replacements. These are caused by single base substitutions in the structural genes. In 1949 Linus Pauling and his colleagues discovered that the electrophoretic mobility of sickle haemoglobin is different from that of normal haemoglobin.

In 1957 Ingram demonstrated by the technique of “fingerprinting” that sickle hemoglobin and normal haemoglobin differed by a single amino acid substitution at position 6 from the N terminus in the β chain.

The word sickling is derived from the sickle shaped red blood cells present in this condition (Fig. 15.21). In homozygotes under low oxygen supplies most of the erythrocytes lose their normal disc shape and become crescent-shaped or sickled. The sickled cells increase the viscosity of blood.

Their presence in smaller vessels leads to blockage of capillaries and tissue damage. The cells are fragile when exposed to mechanical trauma and easily destroyed in the blood vessels or spleen. This leads to the severe condition of sickle cell anemia. In heterozygotes roughly half the erythrocytes are sickle-shaped and half normal, and the individual is only mildly affected or normal.

Besides sickle haemoglobin a number of variants of haemoglobin have been described in which there are one or more (3, 4 or 5) amino acid substitutions in the β chain. Two of the more common ones are designated HbC and HbE; others are relatively rare.

(c) HPFH:

Normally the synthesis of γ chains of foetal haemoglobin is much reduced in the first few months after birth; instead β and δ chains are synthesised in large amounts so that HbA and HbA2 are produced. A number of persons are found to show hereditary persistence of foetal haemoglobin. The condition does not produce any haematological disorder.