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732 Part VI: The Erythrocyte Chapter 48: The Thalassemias: Disorders of Globin Synthesis 733

cytoplasm of the red cell precursors, whereas exon 3 mutations are asso- TABLE 48–3. δβ-Thalassemias
ciated with full-length but abnormal mRNA accumulation. The different
+
phenotypes of these premature termination codons have been suggested (δβ) -Thalassemia
to reflect a phenomenon called nonsense-mediated RNA decay, a sur- Hgb Lepore thalassemia
veillance system to prevent transport of mRNA coding for truncated Hgb Lepore Washington-Boston
peptides. Presumably this process is active in the case of exon 1 or 2
mutations, in which affected mRNAs are degraded, but is not active in Hgb Lepore Hollandia
the case of exon 3 mutations. 95–97 A complete list of the mutations that Hgb Lepore Baltimore
underlie the dominant β-thalassemias is given in reference 44.
Phenocopies of (δβ) -thalassemia
+
Unstable β-Globin Variants Sardinian δβ-thalassemia
Some β-globin chain variants are highly unstable but are capable of Corfu δβ-thalassemia
forming a viable tetramer. The resulting unstable hemoglobins may pre- Chinese δβ-thalassemia
cipitate in the red cell precursors or in the blood, giving rise to a spec-
trum of conditions ranging from dominantly inherited β-thalassemia to β-Thalassemia with δ-thalassemia
a hemolytic anemia similar to the anemia associated with other unstable (δβ)°-Thalassemia
hemoglobins. The first unstable hemoglobin to be described was hemo- Sicilian
globin Indianapolis. Its structure was characterized by DNA analysis
98
performed on stored autopsy material; however, the original description Indian
proved to be incorrect. 99 Japanese
Spanish
Silent β-Thalassemia
A number of extremely mild β-thalassemia alleles are either silent or Black
almost unidentifiable in heterozygotes (see Table 48–2). Some alleles Eastern European
are in the region of the promoter boxes of the β-globin gene, but others Macedonian
involve the CAP sites or the 5′ or 3′ untranslated regions. These alleles
7,44
usually are identified by finding a form of β-thalassemia intermedia in Turkish
which one parent has a typical thalassemia trait and the other parent Laotian
appears to be normal but, in fact, is a carrier of one of the mild β-tha- Thai
lassemia alleles.
( γδβ)°-Thalassemia
A
β-Thalassemia Mutations Unlinked to the B-Globin Gene Indian
Cluster German
Several family studies suggest the existence of mutations that result in
the β-thalassemia phenotype but do not segregate with the β-globin Cantonese
genes ; however, their molecular basis has not been determined. Fur- Turkish
100
ther evidence for the existence of novel mutations of this type can be Malay 2
found in reference 7.
Belgian
Variant Forms of β-Thalassemia Black
In several forms of β-thalassemia, the hemoglobin A level is normal Chinese
2
in heterozygotes. Some cases result from “silent” β-thalassemia alleles,
whereas others reflect the coinheritance of β- and δ-thalassemia. 7 Yunnanese
Thai
δβ-THALASSEMIA Italian
The δβ-thalassemias are classified into the (δβ) - and (δβ) -thalassemias Hgb, hemoglobin.
0
+
(Table 48–3). The (δβ) -thalassemias are further divided into (δβ) -tha- note: Details of the molecular pathology of these conditions are given
0
0
lassemia, in which both the δ- and β-globin genes are deleted, and in Refs. 7 and 45.
( γδβ) -thalassemia, in which the γ, δ, and β genes are deleted. Because
G
0
A
many different deletion forms of δβ-thalassemia have been described,
they are further classified according to the country in which they were A
first identified (Table 48–3). rearrangement with two deletions, one affecting the γ gene and the
101
other the δ and β genes. The intervening region is intact but inverted.
(δβ) - and ( γδβ) -Thalassemia Figure 48–7 illustrates some of these conditions.
0
0
A
Nearly all these conditions result from deletions involving varying
+
lengths of the β-globin gene cluster. Many different varieties have been (δβ) -Thalassemia
+
described in different populations (see Table 48–3), although their het- The (δβ) -thalassemias usually are associated with the production of
102
erozygous and homozygous phenotypes are very similar. Rare forms of structural hemoglobin variants called Lepore. Hemoglobin Lepore
7
these conditions result from more complex gene rearrangements. For contains normal α chains and non-α chains that consist of the first 50
example, one form of ( γδβ) -thalassemia, found in Indian populations, to 80 amino acid residues of the δ chains and the last 60 to 90 residues
0
A
does not result from a simple linear deletion but rather from a complex of the normal C-terminal amino acid sequence of the β chains. Thus,
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