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β-Thalassemia is a common genetic disorder caused by mutations in β-globin gene that results in reduced β-globin production. There are more than 200 different mutations that have been reported till date affecting the diverse levels of β-globin gene expression and causing β-thalassemia. Nucleotide substitutions and frameshift insertion-/deletion-type mutations interfere with the molecular mechanism like transcription of the β-globin gene, splicing process and translation of mRNA of β-globin gene, thus resulting in either absence or reduction of synthesis of β-globin chains. Molecular analysis is a must for all thalassemia patients. Definitive diagnosis and counseling of these patients will help in better management of disease.
Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
*Address all correspondence to: poonam.tripathi90@gmail.com
1. Introduction
1.1 Thalassemia
The thalassemia syndromes are inherited blood disorder caused by mutations in either alpha or beta gene that decreases the synthesis of either alpha or beta globin chains [1]. This results in ineffective erythropoiesis, hemolysis, and ultimately leading to a variable degree of anemia [2]. The main types of thalassemia reported on the basis of the type of globin chains are affected, grouped as α, β, δβ, γδβ, δ, γ and εγδβ thalassemia [3].
In the alpha (α)-thalassemia, there is reduced production or absence of α-globin subunits, whereas in the beta (β)-thalassemia, there is reduced production of β-globin subunits. The β-thalassemia can be clinically classified according to the degree of severity i.e., the beta-thalassemia carrier state, thalassemia intermedia and thalassemia major (TM) [4]. Thalassemia trait or thalassemia carrier type is asymptomatic one, whereas thalassemia intermedia is more severe form than trait and they occasionally need blood transfusions, while a person with thalassemia major is transfusion dependent severe form of disease and to sustain life need regular blood transfusions (Table 1) which later in life develop secondary complications like iron overload, subsequent tissue damage and oxidative stress [5, 6].
Developmental stages
Hemoglobin
Embryonic
Hb Grower1 (ζ2ɛ2)
Hb Grower2 (α2ɛ2)
Hb Portland 1 (ζ2β2)
Hb Portland 2 (ζ2γ2)
Fetal
HbF (α2γ2)
Adult
HbA (α2β2
HbA2 (α2δ2)
Table 1.
Different types of hemoglobin at various developmental stages of human.
Hemoglobin is a tetramer composed of 2-alpha (α)-globin and 2-beta (β)-globin chains working in combination with heme to transport oxygen in the blood (Figure 1). It is iron containing protein, synthesized inside immature erythrocyte in the red bone marrow. The globin polypeptides bind heme molecule, which in turn allows the hemoglobin in erythrocytes to bind oxygen reversibly and transport it from the lungs to other part of body [7, 8].
Figure 1.
Structure of hemoglobin [2].
The main hemoglobin type is HbA in normal adult constitute about 98% and contains two alpha and two beta globin chains (α2β2). The minor type HbA2 constitute less than 3% of the adult hemoglobin consists of two alpha chains and two delta chains (α2δ2). HbF is predominant hemoglobin sub-type, found only during fetal life and consist of two alpha and two gamma (γ) subunits (α2γ2) [9, 10].
In vertebrates, there are typically several forms of Hb differing in composition of polypeptide chains and for oxygen transport under special conditions in various stages of human development. The developmental changes in Hb production are brought by differential activation of globin genes, which is largely determined at level of transcription. This process is known as hemoglobin switching [11].
During early stages of human development, embryonic Hb is expressed in RBC progenitors, which develops in the yolk sac. This Hb molecule consists of two hetero dimmers of epsilon (ε) and zeta (ζ)-globin chains [12]. The first switch in globin composition occurs as the site of erythropoiesis changes from the yolk sac to the fetal liver at 12 weeks post-conception period. Production of the embryonic form (Hb Portland-2 (ζ2β2), Hb Portland-1 (ζ2γ2), Hb Gower-1 (ζ2ɛ2), Hb Gower-2 (α2ɛ2) is downregulated, and it is replaced by fetal hemoglobin (HbF) containing α- and γ-globin chains (Table 1) [6, 13, 14] and by 17 weeks, only 1% of cells continue to express ζ-globin [15]. The second switch occurs approximately 6 weeks after birth: where the levels of fetal γ-globin decline and are replaced with adult hemoglobin (HbA). HbF makes up less than 1% of total hemoglobin in most individuals by 1 year of age [3]. The embryonic and adult α gene share 58% homology at amino acid level [16].
The globin gene clusters show variability in their base composition and are organized into alpha globin gene cluster and beta globin cluster.
4.1 Alpha (α) globin gene cluster
The α-globin gene cluster is located on the short arm of Chromosome 16 (16p13.3). The cluster includes three protein coding functional genes (α1, α2, and ζ2) and spans about 30 kb, and the genes are arranged in order as per their expression during developmental stages in human beings [17, 18].
The α1 and α2 gene are highly homologous and encode an identical protein and differs only in the sequences of non-coding regions [17, 19]. The α-globin gene codes for 141 amino acids and consist of 3 exons separated by two introns (Figure 2). The length of IVS 1 in both α 1 and α 2 gene is same having 117 nucleotides whereas IVS II of α1 consist of 149 and α2 is of 142 nucleotides.
Figure 2.
Alpha globin gene cluster [20].
4.2 Beta (β) globin gene cluster
The β-globin gene cluster is located along a 60-kb segment of the short arm of chromosome 11 (11p15.5) and contains five functional genes (β, δ, Gγ, Aγ, and ε) and one pseudogene (Figure 3). The genes are arranged in the order in which they are expressed during different developmental stages [21]. The regulatory sequences contain four (HS-1 to HS-5) erythroid specific DNAse hypersensitive sites (HSs) known as locus control region (LCR), which is required for DNA-protein interaction. The HBB gene, spans about 1.6 Kb, contains three exons (coding regions) and two introns with 5’and 3’untranslated regions (UTRs). The HBB gene, spans about 1.6 Kb, consist of three exons, interrupted by two introns. The HBB gene is regulated by an adjacent 5′ promoter in which a TATA, CAAT, and duplicated CACCC boxes are located. A major regulatory region, containing a strong enhancer, 50 Kb from the beta globin gene [22]. This region, locus control region (LCR), contains four (HS-1 to HS-4) erythroid specific DNAse hypersensitive sites (HSs), which are involve in DNA-protein interaction. Each HS site is constituted by a combination of several DNA motifs interacting with transcription factors, among which the most important are GATA-1 (GATA indicates the relative recognition motif), nuclear factor erythroid 2, erythroid Krüppel-like factor [23]. The importance of LCR for the control of the beta-like globin gene expression has been discovered by studying a series of naturally occurring deletions that totally or partly remove the HS sites and result in the inactivation of the intact downstream beta globin gene. Several transcription factors bind and regulate the function of the HBB gene, the most important of which is erythroid Krüppel-like factor 1 (KLF 1), which binds the proximal CACCC box [21, 22].
Figure 3.
Beta globin gene cluster [20].
Each gene cluster consist of the structural genes that are separated on both their 3′ and 5′ ends by variable stretches of non-coding DNA containing several types of regulatory sequences [23, 24, 25].
Promoter elements are essential for the binding of messenger RNA polymerase and the initiation of transcription. HBB is immediately preceded by its promoter region. There are five main motifs in HBB’s promoter region:
BRE at −37 GGGCTGG
TATA box at −31 CATAAAAG
Inr at +1 TTACATT
MTE at +27 ACAACTG
DPE at +32 AGCAA
Enhancer and silencer elements stimulate or repress transcriptional activity depending on the array of proteinaceous “transcription factors” to which they are bound and which have two main motifs: the CAT BOX of the pattern CCAAT, and the CACC box of the pattern CACCC [26].
The Locus Control Region (LCR) functions as a “master switch.” Both globin gene clusters (alpha and beta globin) possess a LCR, located many kilobases upstream of the HBB and HBA gene. The LCR appears to interact with a combination of transcription factors at the onset of erythroid maturation in such a way as to enhance access of the transcriptional machinery and other transcriptional factors to the promoters, enhancers, and silencers within the gene complex. LCR function is absolutely required for expression of globin genes at the extraordinary high levels needed for normal hemoglobin synthesis [25].
Thalassemia is characterized by decrease or absence production of α- or β-globin chains, which result in α- or β-thalassemia [25]. More than 400 different types of deletional and non deletional types of mutations in α- or β-globin genes have been reported till date with diverse clinical manifestations, ranging from asymptomatic to fatal anemia [26].
β-Thalassemia (complete absence of hemoglobin subunit beta) alleles result from nonsense, frameshift, or splicing mutations.
β+-Thalassemia alleles are produced by pathogenic variants in the promoter area (either the CACCC or the TATA box), the polyadenylation signal, or the 5′ or 3′ untranslated region, or by splicing abnormalities.
The complex β-thalassemia (delta-beta- and gamma-delta-beta-thalassemia) results from deletion of variable part of HBB gene cluster.
β-Thalassemia also caused by deletion of the LCR regions of HBBgene.
In rare cases of the β-thalassemia mutations reported beyond the β-globin gene cluster.
5.1 Gene deletions
Deletion of one or more alpha globin genes is the most common mechanism responsible for alpha thalassemia in Asian and Mediterranean populations. On the other hand, complete deletion of the beta globin gene is rarely reported, as part of larger gene rearrangement lesions. Rare cases of beta thalassemia are caused by partial beta globin gene deletions and interstitial deletions.
Large deletions within the gene clusters—The “classical” clinically harmless forms of Hereditary Persistence of Fetal Hb (HPFH) appear to arise from deletional events that remove large regions of DNA from the beta gene cluster. In these cases, 50–100 kilobase long segments of DNA are deleted from downstream regions of the beta globin gene cluster. These deletions remove the delta and beta globin structural genes [27].
Persistence of very high levels of fetal hemoglobin synthesis in adult life appears to occur in those cases in which the gene deletion brings a highly active enhancer element into close proximity with the remaining gamma globin gene. This enhancer, usually insulated from the globin gene cluster, provides for high levels of gamma globin gene expression and persistence of Hb F in adult life [27, 28].
Other deletions involving this region cause mild-to-moderate forms of thalassemia in which both delta and beta globin synthesis are absent (delta-beta thalassemia). The clinical pattern seems to depend on the size and location of the downstream deletions; each brings new DNA, with varying enhancer effects, in close proximity to the remaining genes of gamma [29].
Deletions of LCR—these cases are very rare, but extremely informative forms of both beta and alpha thalassemia have been discovered to arise from gene deletion events that remove the locus control region (LCR) sequences. The classical mutation, reported in families, was associated with total absence of beta globin synthesis, even though the beta globin gene and its surrounding promoters and enhancers were found to be normal in structure [30]. The chromosome responsible for this form of thalassemia was found to have undergone a large deletion many thousand bases upstream of the structural genes, through which the critical LCR sequences were lost. Thus the LCR played critical role by permitting expression of the globin genes during erythropoiesis [31].
These events are associated with biochemical and clinical features of hereditary persistence of fetal Hb (HPFH) with the added presence of the structural variant, Hb Kenya. The persistence of high levels of fetal hemoglobin synthesis into adult life may arise because of the removal of stage selector elements and silencers normally positioned between the gamma and delta genes, and the closer apposition of a strong beta globin gene enhancer normally located at the 3′ side of the beta gene to the G (gamma) and Kenya genes. Hb Kenya is rare; the anti-Kenya state has yet not been identified [32, 33].
5.2 Mutations affecting transcription
Alpha and beta thalassemia have been found to arise from mutations that alter known promoter or enhancer sequences for alpha or beta globin genes [28]. These point mutations alter the efficiency of the promoter or enhancer, while others are small gene deletions or rearrangement that disrupts their spatial integrity [29].
5.3 Mutations affecting Pre-mRNA splicing
Many mutations have been described that disrupt normal splicing of the mRNA precursor. Among these are some of the most common forms of beta thalassemia and more common varieties of “non-deletion” forms of alpha thalassemia [21, 34].
5.4 Alteration of canonical splice signals
Some thalassemic splicing mutations directly disrupt the canonical “splicing signals” used to mark the beginning and end of each intron so that normal splicing can occur. These short sequences are required by the splicing machinery. They signify the places at which excision of the intron, and ligation together of the flanking exons, should occur [34, 35].
Certain bases in these splicing signals are “invariant”, such as the GT dinucleotide required at the 5′ beginning of the intron and the AG dinucleotide required at the 3′ end of the intron. The several bases to either side of these invariant nucleotides are consensus sequences within which alteration of the base will change the efficiency with which the site is used [36]. Thus, mutations altering these nucleotides can abolish normal splicing or reduce it to a variable degree. Mutations that alter the consensus splice sites reduce production of alpha or beta globin mRNA; the pre-mRNA molecules which are not properly spliced appear to be catabolized rapidly, so that abnormal mRNA products do not accumulate [37].
In some cases, pre-mRNAs that are not spliced at the proper sites are spliced elsewhere by activation of “cryptic” sites, resulting in the production of structurally abnormal, usually non-functioning messenger RNAs [35]. The molecular basis for variability with which mutations reduce the efficiency of normal splicing, or generate production of detectable abnormally spliced products, remains poorly understood and needs to be investigated.
5.5 Activation of cryptic splicing sites
Another class of splicing mutations, one of which produces a very common form of thalassemia in the Mediterranean region, includes those in which the mutation activates a “cryptic” splice site. These mutations are not located within the consensus sites at either end of introns. Rather, base substitution, small deletions, or small insertions of DNA, can convert a site within an exon or intron that normally bears only a slight resemblance to a splice site into one containing much stronger consensus signal [37, 38]. Depending upon the consequential “strength” of the signals, the splicing apparatus will utilize that site instead of normal site in a greater or lesser percentage of the pre-mRNA molecules being spliced. At least two spliced mRNA products result, accumulating in varying percentages, depending on efficiency with which the cryptic site is used and the stability of the abnormally spliced product [29, 38].
5.6 Altered mRNA translation and stability
Mutations that create a premature translation termination codon (nonsense codon) account for the most common forms of thalassemia, in terms of numbers of patients affected. These mutations create translation stop signals prematurely, so that the complete beta globin polypeptide is never made. In the most common type of thalassemia, globin fragments are highly unstable, resulting in the accumulation of protein synthesized from the mutated gene (i.e., beta (0) thalassemia) [38]. As a result, patients homozygous for this defect cannot make any beta chains and suffer from a severe form of beta thalassemia [27].
Premature translation termination can occur by base substitution or deletion of bases in an exon, producing so called “frame shift” mutations. The inserted or deleted stretch of DNA contains a number of bases that is an exact multiple of three, so “open” translation reading frame is maintained. So, the insertion or deletion will cause the ribosome to begin reading the codons out of the normal reading frame. One consequence of this “frame shift” mechanism is that the probability that a UAA, UAG, or UGA translation termination codon will be encountered with the shifted reading frame within 50 or so bases downstream [38, 39].
In the normal reading frame, these three bases (UAA, UAG, UGA) are usually divided among two codons, and thus never “read” as a stop codon by the ribosome. In the shifted reading frame, the three bases will appear as a single codon and translation ceases. Thus frame shifting results into premature translation termination. A reason for occurrences of both alpha and beta thalassemia mutations.
The physiologic consequences of translation termination are very clear; functional globin not synthesized and thalassemia results. Less obvious is the phenomenon that these prematurely terminated mRNAs accumulate in greatly reduced amounts. The reason behind impaired accumulation is not clear, since their transcription, processing, and stability elements are intact. Recent research work has shown that there are normal cell defense mechanisms to eliminate abnormally translated mRNAs. They probably exist in order to guard against the accumulation of truncated protein products, which have the potential to interact abnormally with other proteins and damage cells. This protective phenomenon is called nonsense-mediated decay.
Curiously, premature stop codons that occur in the final exon of either the alpha or beta globin gene accumulate at nearly normal levels. Moreover, the truncated polypeptides also accumulate stably and in significant amounts. It appears that the process of nonsense-mediated decay affects only those mRNAs in which the premature stop codon occurs in the first or second exons. This has been found in other gene systems as well. Indeed, there is increase in substantiation that nonsense-mediated decay and mRNA splicing are interactive processes [32].
A few, comparatively uncommon, mutations that cause thalassemia by disrupting the structure of the fully translated globin product. That appears to interfere with normal folding of the globin peptide to form stable dimers or tetramers. In each case, the abnormal globin generates inclusion bodies and produces a thalassemia phenotype. The final common pathway for these mutations is similar to that of the dominant form of thalassemia due to nonsense codons in the final exon. In all circumstances, accumulation and generation of substantial amounts of the abnormal protein results in formation of inclusion bodies [34, 35, 38].
Thalassemia arises from well over 400 mutations that, in the cumulative, affect every step required for successful production of the large amounts of Hb needed for normal red cell homeostasis. The mutations accounting for most of the thalassemia patients around the world are those affecting translation termination and mRNA splicing. Gene deletions and rearrangements, and defects affecting transcription, mRNA stability, or Hb assembly are uncommon or occur rarely.
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Written By
Poonam Tripathi
Submitted: 17 June 2022Reviewed: 26 July 2022Published: 18 October 2022
Open access peer-reviewed chapter
