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728 Part VI: The Erythrocyte Chapter 48: The Thalassemias: Disorders of Globin Synthesis 729

hypothesis, elucidation of some of the extremely complex population in reviews. 19,23,24 Although there are less data of this kind available for
genetics underlying polymorphic systems such as the thalassemias has the β-thalassemias, there is strong indirect evidence that their high fre-
been possible only with the advent of recombinant DNA technology. quency has also been maintained by protection against P. falciparum
In each of the high-frequency areas for the β-thalassemias, a few malaria.
common mutations and varying numbers of rare mutations are seen
(see Fig. 48–1). Furthermore, in each of these regions the pattern of ETIOLOGY AND PATHOGENESIS
mutations is different, usually found in the context of different haplo-
types in the associated β-globin gene cluster. 11,14,15 Similar observations GENETIC CONTROL AND SYNTHESIS OF
7,11
have been made in the α-thalassemias (see Fig. 48–2). These studies
suggest the thalassemias arose independently in different populations HEMOGLOBIN
and then achieved their high frequency by selection. Although some The structure and ontogeny of the hemoglobins are reviewed in Chaps.
movement of the thalassemia genes may have resulted from drift, inde- 7 and 49, respectively. Only those aspects with particular relevance to
pendent mutation and selection undoubtedly provide the overall basis the thalassemia problem are discussed here.
for their world distribution. Early studies in Sardinia, showing that Human adult hemoglobin is a heterogeneous mixture of proteins
β-thalassemia is less common in the mountainous regions where malar- consisting of the major component hemoglobin A and the minor com-
ial transmission is low, supported Haldane’s suggestion that β-thalas- ponent hemoglobin A , which constitutes approximately 2.5 percent of
2
semia reached its high frequency because of protection against malarial the total. In intrauterine life, the main hemoglobin is hemoglobin F. The
infections. For many years these data remained the only convincing structure of these hemoglobins is similar. Each consists of two sepa-
16
evidence for a protective effect. However, later studies using malaria rate pairs of identical globin chains. Except for some of the embryonic
endemicity data and globin-gene mapping showed a clear altitude-re- hemoglobins (see below), all normal human hemoglobins have one pair
lated effect on the frequency of α-thalassemia in Papua New Guinea. of α chains. In hemoglobin A, the α chains are combined with β chains
In addition, a sharp cline (a gradual change of species phenotype over (α β ), in hemoglobin A with δ chains (α δ ), and in hemoglobin F with
2 2
a geographical area) in the frequency of α-thalassemia has been found γ chains (α γ ). 2 2 2
2 2
in the region stretching south from Papua New Guinea through the Human hemoglobin shows further heterogeneity, particularly in
island populations of Melanesia to New Caledonia. This is mirrored by fetal life, and this has important implications for understanding the
17
a similar gradient in the distribution of malaria. The effect of drift and thalassemias and for approaches to their prenatal diagnosis. Hemo-
founder effect in these island populations has been largely excluded by globin F is a mixture of molecular species with the formulas α γ 136Gly
2 2
showing that other DNA polymorphisms have a random distribution and α γ 136Ala . The γ chains containing glycine at position 136 are desig-
2 2
through the region, with no evidence of a cline similar to that charac- nated γ chains. The γ chains containing alanine are called γ chains. At
A
G
terizing the distribution of α-thalassemia and malaria. birth, the ratio of molecules containing γ chains to those containing γ
A
G
Firm evidence for protection of individuals with mild forms of chains is approximately 3:1. The ratio varies widely in the trace amounts
α -thalassemia against Plasmodium falciparum malaria has been pro- of hemoglobin F present in normal adults.
+
vided. In a case-control study performed in Papua New Guinea, the Before week 8 of intrauterine life, three embryonic hemoglobins—
homozygous state for α -thalassemia offered approximately 60 percent Gower 1 (ξ ε ), Gower 2 (α ε ), and Portland (ξ γ )—are present. The ξ
+
2
2 2
2
2 2
protection against hospital admittance because of serious complications and ε chains are the embryonic counterparts of the adult α and β and γ
18
of malaria, notably coma or profound anemia. Similar levels of pro- and δ chains, respectively. ξ-Chain synthesis persists beyond the embry-
tection by α-thalassemia against P. falciparum malaria have been found onic stage of development in some of the α-thalassemias. Persistent
in several different African populations. However, it is becoming clear ε-chain production has not been found in any of the thalassemia syn-
19
that there are complex genetic epistatic interactions between protective dromes. During fetal development, an orderly switch from ξ- to α-chain
polymorphisms of this kind. For example, although α-thalassemia and and from ε- to γ-chain production occurs, followed by β- and δ-chain
the sickle cell trait both offer strong protection against P. falciparum production after birth.
malaria, in those who inherit both traits, the protection is canceled Figure 48–3 shows the different human hemoglobins and the
20
out and they are fully susceptible to the disease. Interactions of this arrangements of the α-gene cluster on chromosome 16 and the β-gene
type will have an important effect on the gene frequency of protective cluster on chromosome 11.
polymorphisms in countries in which more than one exists in the same
population. Globin Gene Clusters
There is growing evidence that both immune and cellular mecha- Although some individual variability exists, the α-gene cluster usually
nisms may underlie these protective effects of different red cell polymor- contains one functional ξ gene and two α genes, designated α and α . It
2
1
phisms against malarial infection. Followup studies of cohorts of babies also contains four pseudogenes: ψξ , ψα , ψα , and θ . These four pseu-
9,10
1
1
1
2
with α-thalassemia suggest that, in the first year of life, they are more dogenes are remarkably conserved among different species. Although it
prone to Plasmodium vivax and P. falciparum malaria. Because there is appears to be expressed early in fetal life, its function is unknown. It
evidence for cross-immunization between these two species, it is possi- likely does not produce a viable globin chain. Each α gene is located in a
ble that this effect induces early immunization that may result in babies region of homology approximately 4 kb long, interrupted by two small
with α-thalassemia being more resistant to P. falciparum malaria later in nonhomologous regions. 25–27 The homologous regions are believed to
life. At the cellular level there is no evidence that α-thalassemia has any result from gene duplication, and the nonhomologous segments are
21
effect on the rates of parasite invasion and growth in red cells. However, believed to arise subsequently by insertion of DNA into the noncoding
parasitized α-thalassemic red cells are more susceptible to phagocyto- regions around one of the two genes. The exons of the two α-globin
sis in vitro, and are less able than normal cells to form rosettes, an in genes have identical sequences. The first intron in each gene is identical.
vitro phenomena whereby uninfected cells bind to infected cells that is The second intron of α is nine bases longer and differs by three bases
strongly associated with severity of infection, and express low levels of from that in the α gene. 1 27–29 Despite their high degree of homology, the
2
complement receptor 1, which is required for rosette formation. These sequences of the two α-globin genes diverge in their 3′ untranslated
22
highly complex immune and cellular interactions are discussed in detail regions 13 bases beyond the TAA stop codon. These differences provide
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