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© Borgis - Postępy Nauk Medycznych 7/2012, s. 589-594
Katarzyna Koza, *Jadwiga Fabijańska-Mitek, Adrianna Łoniewska-Lwowska
Hemoglobinopatie i talasemie – podłoże genetyczne oraz diagnostyka z zastosowaniem technik biologii molekularnej
Hemoglobinopathies and thalasemias – genetic basis and molecular diagnosis**
Department of Immunohaematology, Medical Centre of Postgraduate Education, Warsaw
Head of Department: Jadwiga Fabijańska-Mitek, PhD
Hemoglobinopatie i talasemie są chorobami genetycznymi, które mają związek z mutacjami w genach kodujących białka globiny, najczęściej w genach α i β globiny. Hemoglobinopatie wynikają z zaburzeń struktury białka hemoglobiny. W talasemii dochodzi do obniżenia syntezy określonych łańcuchów globiny. Mutacje dotyczące genu γ globiny prowadzą do wzrostu stężenia hemoglobiny płodowej u dorosłych, a taki stan nazwano zespołem wrodzonego przetrwania hemoglobiny płodowej (HPFH). W związku z występowaniem hemoglobinopatii i talasemii w rejonach świata, w których wcześniej nie były wykrywane, w tym w Polsce, rośnie potrzeba opracowania coraz lepszych metod diagnostycznych oceniających geny kodujące białka globiny. Powinny one wykrywać powszechne mutacje, ale także mutacje rzadkie i powstające de novo. Ich zastosowanie jest również ważne w diagnostyce prenatalnej, szczególnie w populacjach, w których talasemie i hemoglobinopatie są częste.
Hemoglobinopathies and thalasemias are genetic disorders connected with the presence of mutations in genes coding globin proteins, mainly in genes coding α and β globin. Hemoglobinopathies are connected with haemoglobin protein alterations. Thalasemias are caused by decreased production of specific globin chains. Mutations in γ globin gene cause an increase in haemoglobin F concentration in adults, and this condition was called hereditary persistence of fetal haemoglobin (HPFH). Taking into consideration the fact that this disorders are presently common in the areas (including Poland), where they have not been previously often detected, there is increasing need to develop better diagnostic methods, evaluating genes coding globin proteins. They should detect not only common mutations, but also rare and de novo mutations. Their application is also important in prenatal diagnosis, particulary in populations with high frequency of thalasemias and hemoglobinopathies.
Anaemias are heterogeneous group of disorders, connected with red blood cell (RBC) count and/or haemoglobin concentration decrease. A large group are haemolytic anemias – congenital or acquired diseases caused by various intra- and extracellular factors. Each one of this disorders is connected with shorten lifespan of RBCs and accelerated removal of this cells. They may be the result of haemoglobin synthesis disturbances, caused by mutations in one or more genes coding globing chains. Congenital haemolytic anaemias connected with this variations are divided into two groups. The first one contains disorders in which mutation causes disturbance in aminoacid sequence of globin polypeptide chain and that gives abnormal type of haemoglobin with impaired functions; this group of diseases is called haemoglobinopathies (1). The second group are thalassemias, in which mutation in one or more globin genes leads to absence or decrease in globin protein synthesis. Excessive globin chains damage red blood cells, and that in consequence shortens RBCs lifespan (2, 3).
It was long believed, that haemoglobinopathies and thalassemias are found only in tropical and subtropical regions. High degree of carrier-state in this areas was connected with mechanisms protecting against Plasmodium and malaria (4). In recent years it was noticed that frequency of this disorders is increasing in different regions, like North America, Great Britain, Australia (5) and Germany (1). Cases of thalassemia α and β are also more often described in Poland (6-10). It is related to accelerated migration and increased percentage of mixed marriages, but also to improved diagnostic methods detecting this disorders. It is important to diagnose thalassemia and describe the number and the type of mutations not only to begin the appropriate therapeutic action, but also to determine the carrier state in patients in reproductive age. This strategy is particularly important in regions, where thalassemias are very common and the risk of having a partner with globin disorder is high (11, 12).
Haemoglobin structure and coding of globin chains
Haemoglobin (Hb) is red blood cell protein, and its basic function is oxygen transport. Haemoglobin particle is built of four subunits covalently bound. Each subunit is composed of polipeptyde chain, globin molecule, bound with haeme. The haeme group is the same in all Hb types and is built of porphyrin ring with iron atom in the centre (13). Different kinds of haemoglobin contain various protein chains. Particular globin types are named with Greek alphabet letters α, β, γ, δ, ε and ζ. The correct haemoglobin kinds in adults are HbA (2α2β, 97%), HbA2 (2α2δ, 2%) and remains of foetal Hb, HbF (2α2γ, 1%) (3). The regular set of haemoglobin types during human life and pathology in thalassemias and haemoglobinopathies is shown in table 1.
Table 1. The types of regular and abnormal haemoglobin in healthy human and in the most common thalassemias and haemoglobinopathies (according to [22, 36]).
 Haemoglobin content
HbA (2α2ß)HbA2 (2α2δ)HbF (2α2γ)Other Hb
Embryo absentabsentabsentGower I (2ζ2ε)
Gower II (2α2ε)
Portland (2ζ2γ)
Healthy foetusabout 15%absentabout 85%absent
Healthy adultabout 97%about 2%about 1%absent
α thallasemia trait
HbH disease
Hydrops fetalis related to Hb Bart’s
about 2%
2% or less
about 1%
1% or less
Hb Bart’s (4γ) up to 10% at birth
HbH (4β) 5-30% Hb Bart’s up to 30% at birth
HbH 5-10% Hb Bart’s 90-95%
Thallasemia β minor
Thalassemia β intermedia
Thalassemia β major
HbE heterozygotes
HbE homozygotes
about 5%
HbE 30-35%
HbE up to 95%
HbC heterozygotes
HbC homozygotes
slight increase
slight increase
slight increase
HbC 30-40%
HbC up to 95%
HbD heterozygotes
HbD homozygotes
HbD 45-50%
HbD up to 95%
Sickle cell anaemia heterozygotes
Sickle cell anaemia homozygotes
about 3%
about 3%
about 1%
about 7%
HbS 30-45%
HbS up to 90%
All genes coding globin chains are gathered in two clusters: cluster α on chromosome 16, containing genes coding α and ζ globin; cluster β on chromosome 11, containing genes coding β, γ, δ and ε globin (14). Expression of all genes in each cluster is controlled by one regulatory element, α-MRE (major regulatory element) controlling α and ζ genes, and β-LCR (locus control region) controlling β, γ, δ and ε genes. The regulatory element affects the promoter of one of the genes in the cluster and enhances its expression. Expression of other genes in this cluster remains very low or is entirely inhibited (14-17). During foetal life occurs double haemoglobin synthesis switching (17). Around 10 week of foetal life stops the expression of ε and ζ globin, and synthesis of embryonic haemoglobins (Gower I, Gower II and Portland), and the main Hb becomes foetal haemoglobin (HbF). The second haemoglobin switching occurs shortly before birth. Then the γ globin gene expression is silenced and β globin gene expression is enhanced. As a result, synthesis of γ globin and HbF decreases, and synthesis of β globin and HbA increases (18). This process lasts until around six month after birth.
Genetic basis of haemoglobinopathies and hereditary persistence of fetal hemoglobin
Haemoglobinopathies are diverse group of disorders, with different clinical symptoms and genetic background. Mutations occur usually in β globin gene, less frequently in α globin and other genes. In every case mutation leads to synthesis of a new protein, in varying degrees different from the correct globin chain. A large group of haemoglobinopathies are anaemias connected with point mutations in β globin gene. The examples are haemoglobinopathies C, D and E, in which irregular forms of haemoglobin are produced, respectively, HbC, HbD and HbE (19). In heterozygotes there is about 30-50% of this abnormal haemoglobin, while in homozygotes they can present as much as 90% of total Hb. HbE is most frequent in South-East Asia, where percentage of carriers reaches 60% in some countries (20), HbC in West Africa (1), HbD in South Asia (21). Heterozygotes are carriers of one damaged gene and have no clinical symptoms. Homozygotes suffer from haemolysis, but it is usually mild and does not require therapy (22). Interesting case of haemoglobinopathy is congenital methaemoglobinaemia or haemoglobinopathy M. Mutation occurs in α or β globin gene, and protein is altered in the region next to the iron atom. Iron is stabilized in Fe3+ form and that gives abnormal form of Hb- methaemoglobin, incapable of carrying oxygen (23).
Mutations causing haemoglobinopathies are not only point mutations. There are described cases of large deletions and the example is haemoglobinopathy connected with presence of Hb Lepore. It is abnormal haemoglobin, with no regular function and is a result of deletion of large regions of β and δ globin genes. The polypeptide chain of Hb Lepore is coded by the remains of this two genes. Homozygotes have symptoms similar to signs of β thalassemia major described below, heterozygotes have mild symptoms similar to β thalassemia minor or intermedia (24). A large group of haemoglobinopathies are anaemias connected with presence of unstable haemoglobins (for instance Hb Bristol and Hammersmith). There are described more than 220 mutations leading to this kind of haemoglobinopathies, and most of them is a consequence of mutation in β globin gene. Unstable haemoglobins are denaturated in high temperature and globin chains are precipitated as so-called Heinz bodies. Red blood cells have less flexibility and shorten lifespan, and that gives anaemia of varying degrees of severity (22).
The most common haemoglobinopathy and one of the most common results of congenital RBC defects is sickle cell anaemia, SCA. This disease was first described in 1910 and it was one of the first disorders described on molecular level. Sickle cell anaemia is inherited in the autosomal recessive way. Mutation occurs in β globin gene, the second nucleotide of the sixth codon, adenine, is replaced by thymine. As a consequence, in β globin protein chain, in 6 position, glutamic acid is replaced by valine. Exchange of one aminoacid results in formation of abnormal form of haemoglobin- HbS, which may present as much as 90% of total Hb in homozygotes. The HbS particle is more “sticky” than the correct HbA molecule. Polypeptide chain of HbS tends to create long polymers, damaging red blood cells. Forming of sickle RBCs is a typical symptom of SCA. This erythrocytes are elongated and stiff, are unable to perform their function and have significantly shorten lifespan. They also tend to form blockages in small blood vessels, and that results in tissues anoxia and strong pain (22).

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otrzymano: 2012-05-07
zaakceptowano do druku: 2012-06-04

Adres do korespondencji:
*Jadwiga Fabijańska-Mitek
Department of Immunohaematology, Medical Centre of Postgraduate Education
ul. Marymoncka 99/103, 01-813 Warszawa
tel.: +48 (22) 569-38-20
e-mail: biofizyka@cmkp.edu.pl

Postępy Nauk Medycznych 7/2012
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