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The Molecular Basis of A-Thalassemia

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The Molecular Basis of A-Thalassemia Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press The Molecular Basis of a-Thalassemia Douglas R. Higgs MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom Correspondence: [email protected] The globin gene disorders including the thalassemias are among the most common human genetic diseases with more than 300,000 severely affected individuals born throughout the world every year. Because of the easy accessibility of purified, highly specialized, mature erythroid cells from peripheral blood, the hemoglobinopathies were among the first tractable human molecular diseases. From the 1970s onward, the analysis of the large repertoire of mutations underlying these conditions has elucidated many of the principles by which mutations occur and cause human genetic diseases. This work will summarize our current knowledge of the a-thalassemias, illustrating how detailed analysis of this group of diseases has contributed to our understanding of the general molecular mechanisms underlying many orphan and common diseases. he molecular basis of a-thalassemia has been tomosthumangeneticdiseasesandfurtheranal- Textensively reviewed many times in the past ysis of these uniquely well-characterized gene (Higgs et al. 1989; Harteveld and Higgs 2010), clusters will continue to elucidate important so why should we take the opportunity to revisit new mechanisms by which mammalian genes this topic; what can this contribute to our fur- are normally switched on and off during cell fate ther understanding of how globin synthesis may decisions, and how this is perturbed in both be perturbed and how this relates more gener- common and orphan genetic diseases. ally to human genetic disease? In my view, de- An argument that is commonly put forward spite the extensive new knowledge of human is that the globin genes are very unusual, atypical www.perspectivesinmedicine.org genetic disease that is being obtained from the genes and what we learn from them may be ex- application of new generation sequencing of ceptions to the rule. On the contrary, it is hard to material from patients with a wide range of in- think of a single example in which what has been herited and acquired human genetic diseases, established from analyzing the globin genes (in- many of the principles by which mutations cause volving enhancers, locus control regions, boun- human disease have been established for many dary elements, promoters, RNA processing, and years since the application of modern molecular numerous aspects of protein translation, struc- and cellular biology to the globin gene disor- ture, and function) has been limited to these ders. It is underrecognized that what we have genes rather than establishing general principles learned from the hemoglobinopathies applies of mammalian genome organization and how Editors: David Weatherall, Alan N. Schechter, and David G. Nathan Additional Perspectives on Hemoglobin and Its Diseases available at www.perspectivesinmedicine.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a011718 Cite this article as Cold Spring Harb Perspect Med 2013;3:a011718 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press D.R. Higgs this relates to gene expression. Furthermore, the disease traits (Higgs2009a; Williams and Weath- molecular mechanisms by which globin gene erall 2012). Among people originating from mutations arise (chromosomal rearrangements, these areas, compound heterozygotes and ho- telomere truncations, homologous and illegiti- mozygotes for some mutations may have severe mate recombination, gene conversion, copy hematologic phenotypes. When a-globin syn- number variation, nucleotide polymorphism, thesis is reduced to 25% or less, patients may changes in tandem repeats, abnormal methyla- suffer from a moderately severe hemolytic ane- tion, the involvement of antisense RNAs, and mia associated with readily detectable excess b- many more) are now known to be common to globin chains in the form of b4 tetramers (re- many human diseases and yet were first recog- ferred to as HbH); hence, the condition is called nized in the globin gene disorders. Their analy- HbH disease (Chui et al. 2003; Vichinsky 2012). sis has been at the forefront of identifying the When a-globin synthesis is even further reduced mechanisms by which mutations at every level (or even abolished), this gives rise to a severe of gene expression may cause human disease. intrauterine anemia associated with excess g- Rather than being unusual outliers, the glo- globin chains in the form of g4 tetramers (re- bin genes are in most ways, typical mammalian ferred to as Hb Bart’s); hence, this condition is genes, which when mutated cause typical hu- referred to as the Hb Bart’s hydrops fetalis syn- man genetic diseases by common mechanisms drome (BHFS) (Lorey et al. 2001; Vichinsky and have pioneered our understanding of how 2012). The high frequency of a-thalassemia natural mutations cause human genetic disease. trait, HbH disease, and BHFS means that tens In the future, it will be important to contin- of thousands of patient samples have been ana- ue using the knowledge gained from the well- lyzed and that probably most of the natural mu- characterized globin gene disorders to further tations affecting these genes are now known. develop our understanding of the mechanisms Consequently, in most instances, accurate genet- by which both common and orphan human ic counseling and (when appropriate) prenatal genetic diseases may arise. In this article, I sum- testing can be made available in countries where marize some of what we have learned from study- the health care infrastructure is able to support ing mutations of the a-globin cluster and how this. However, even when all known mutations this may provide insight into how we may un- have been excluded, new, often rare but infor- derstandthemechanismsunderlying humange- mative genetic variants are still being found. netic disease in general. THE NORMAL STRUCTURE AND a www.perspectivesinmedicine.org IDENTIFYING INDIVIDUALS WITH EXPRESSION OF THE -GLOBIN CLUSTER a-THALASSEMIA Expression of the a-like and b-like globin Down-regulation of a-globin synthesis causes chains is regulated by clusters of genes on chro- a-thalassemia, which is characterized by under- mosomes 16 and 11, respectively (Higgs and production of fetal (HbF, a2g2) and adult (HbA, Wood 2008; Noordermeer and de Laat 2008). a2b2) hemoglobin (Higgs et al. 1989). The con- The a-like gene cluster is located close to the siderable diversity of mutations that have been telomere of chromosome 16 (16p13.3) includ- identified is explained by the fact that carriers ing an embryonic gene (z) and two fetal/ fora-thalassemia are (to some extent) protected adult genes arranged along the chromosome in from falciparum malaria in a manner that we the order telomere-z-a2-a1-centromere, sur- still do not fully understand (reviewed in Higgs rounded by widely expressed genes (Fig. 1). 2009a; Williams and Weatherall 2012). Conse- The normal cluster is denoted aa. Approx- quently, in tropical and subtropical regions of imately 25–65 kb upstream of the a-globin the world (where malaria is endemic), a-thalas- genes there are four highly conserved noncod- semia reaches very high frequencies, making it ing sequences, or multispecies conserved se- one of the most common of all human genetic quences (MCS), called MCS-R1 to -R4, which 2 Cite this article as Cold Spring Harb Perspect Med 2013;3:a011718 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Molecular Basis of a-Thalassemia 60 k 70 k 80 k 90 k 100 k 110 k 120 k 130 k 140 k 150 k 160 k 170 k 180 k 190 k 200 k 210 k 220 k NPRL3 ξα2 α1 Luc7L MHU genes MPG MCSR1 MCSR2 MCSR3 MCSR4 MCS-R X YZXYZ XYZ box I IIIII α4.2 Deletions - -α3.7 --Med --SEA α-ZF (αα)TM Duplications BS FD Repeats VNTR repeats Classic haplotype SNPs * rSNP Humanized mouse Figure 1. The human a-globin cluster (50-z-a2-a1-30) surrounded by widely expressed genes (MPG, NPRL3, and Luc7L) on chromosome 16 (16p13.3). Below this, the multispecies conserved elements (MCS-Rs) are shown. The X, Y, and Z boxes are the regions of duplication that play a part in the generation of the common a-thalassemias, as discussed in the text. The most common deletions removing one (-a3.7 and -a4.2) or both (--Med and --SEA) a genes and causing thalassemia are shown as horizontal bars, as are the unusual deletions a-ZF and (aa)TM. Duplications of the cluster BS and FD are also indicated. For a full catalog of all deletions that cause a-thalassemia, see Higgs (2009a). At the bottom of the figure the positions of common repeats, variable number random repeats (VNTRs) and single-nucleotide polymorphisms (SNPs) are shown. The region con- taining all SNPs and VNTRs corresponding to the classic haplotype used in population studies (as discussed in the text) is illustrated as a thin horizontal line. The regulatory SNP (rSNP) that creates new functional GATA1- binding sites seen in the Melanesian nondeletional a-thalassemia is shown with an asterisk. The extent of the a-globin locus present in the humanized mouse is shown as a thin line. www.perspectivesinmedicine.org are thought to be involved in the regulation of promoters of the a-like globin genes (Fig. 2). the a-like globin genes (see Fig. 1). It is of inter- Binding of these factors is associated with wide- est that three of these elements (MCSR1–3) spread modifications of the associated chro- lie within the introns of the adjacent wide- matin reflecting activation (e.g., histone acety- ly expressed gene NPRL3 (Kowalczyk et al.
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