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734 Part VI: The Erythrocyte Chapter 48: The Thalassemias: Disorders of Globin Synthesis 735

Figure 48–8. Mechanisms for the produc-
tion of the Lepore and anti-Lepore hemoglo-
bins. Hgb, hemoglobin.

normal hemoglobin A levels, is identical to that of δβ-thalassemia. Dutch deletion first pointed to the possibility of a major control region
103
2
Another condition having the β-thalassemia phenotype, with greater upstream from the β-like-globin gene cluster and ultimately led to the
than 20 percent hemoglobin F in heterozygotes, has been described in discovery of the β-globin LCR.
a Chinese patient in whom defective β-globin chain synthesis appears
to result from an A→G change in the ATA sequence in the promoter HEREDITARY PERSISTENCE OF FETAL
region of the β-globin gene. The increased γ-chain synthesis, which
104
appears to involve both γ and γ cis to this mutation, remains unex- HEMOGLOBIN
A
G
plained. A disorder originally called δβ-thalassemia has been described This heterogeneous group of conditions produces phenotypes very
in the Corfu population. 105,106 The condition results from two mutations similar to those of the δβ-thalassemias, except that defective β-chain
in the β-globin gene cluster: first, a 7201-bp deletion that starts in the production appears to be almost, but in some forms not completely,
δ-globin gene, IVS-2, position 818 to 822, and extends upstream to a compensated by persistent γ-chain production. These conditions are
5′ breakpoint located 1719 to 1722 bp 3′ to the ψβ-gene termination best classified into deletion and nondeletion forms (Table 48–4). In the
codon; and second, a G→A mutation at position 5 in the donor site con- past, the conditions were classified into pancellular and heterocellular
sensus region of IVS-1 of the β-globin gene. The output from this chro- varieties, depending on the intercellular distribution of fetal hemoglo-
mosome consists of relatively high levels of γ chains with very low levels bin. However, this subdivision now appears to bear little relevance to
of β chains. The condition resembles δβ-thalassemia in the homozygous their molecular basis and probably relates more to the particular level of
state, with almost 100 percent hemoglobin F, traces of hemoglobin A, fetal hemoglobin and how its cellular distribution is determined. 7
but no hemoglobin A . Heterozygotes have only slightly elevated hemo- The deletion forms of HPFH are heterogeneous (see Fig. 48–7).
2
globin F levels, with a phenotype similar to “normal A β-thalassemia.” The two African varieties result from extensive deletions of similar
2
length (<70 kb) but with staggered ends, differing phenotypically only
in the proportions of γ and γ chains produced. Another type of
A
G
114
εγδβ-THALASSEMIA HPFH results from misalignment during crossing over between the
These rare conditions 107–113 result from long deletions that begin A γ- and β-globin genes, resulting in production of γβ fusion genes (see
A
upstream from the β-gene complex 55 kb or more 5′ to the ε gene and Fig. 48–8) that combine with α chains to form the hemoglobin variant
terminate within the cluster (see Fig. 48–7). In two cases, designated called hemoglobin Kenya. 115,116 Hemoglobin Kenya is associated with an
112
Dutch 110,111 and English, the deletions leave the β-globin gene intact, increased output of hemoglobin F, although at a lower level than in the
but no β-chain production occurs even though the gene is expressed in deletion forms of HPFH. A theory that adequately explains the phe-
heterologous systems. notypic differences between δβ-thalassemia and the deletion forms of
The molecular basis for inactivation of the β-globin gene cis to HPFH has not been developed. 7
these deletions was clarified by the discovery of the LCR approximately The nondeletion determinants of HPFH can be classified into those
50 kb upstream from the εγδβ-globin gene cluster (see “Genetic Control that map within the β-globin gene cluster and those that segregate inde-
and Synthesis of Hemoglobin” above). Removal of this critical regula- pendently. The former are subdivided into γβ and γβ varieties, indi-
G
+
A
+
tory region seems to completely inactivate the downstream globin gene cating persistent γ- or γ-chain synthesis in association with β-globin
A
G
complex. The Hispanic form of εγδβ-thalassemia results from a dele- production directed by the β gene cis (on the same chromosome) to the
113
tion that includes most of the LCR, including four of the five DNase-1- HPFH determinant. Analysis of the overexpressed γ genes revealed in
hypersensitive sites. These lesions appear to close down the chromatin each case a single-base substitution in the region immediately upstream
domain that usually is open in erythroid tissues and delay replication from the transcription start site. 7,117–120 Clustering of these substitutions
of the β-globin genes in the cell cycle. Thus, although they are rare, the and lack of similar changes in normal γ genes suggest they are respon-
lesions have been of considerable importance because analysis of the sible for persistent hemoglobin F production (Fig. 48–9). This region
Kaushansky_chapter 48_p0725-0758.indd 735 9/18/15 2:57 PM