Page 763 - Williams Hematology ( PDFDrive )

738 Part VI: The Erythrocyte Chapter 48: The Thalassemias: Disorders of Globin Synthesis 739

Figure 48–10. Some deletions of the α-globin gene cluster responsible for α -thalassemia. Deletions: MC, initials of patient; CAL, initials of patient;
0
THAI, Thai; FIL, Filipino; CI, Conway Islands; BRIT, United Kingdom; SA, South Africa; MED, Mediterranean; SEA, Southeast Asian; SPAN, Spanish. The top
line indicates the size of the region in kilobases (K). The second line shows the different genes that constitute the α-globin gene cluster, HS40, the
major regulatory region of the cluster, and the position of other genes in the region. The lines in blue represent the size of the deletions that have
0
been described in α -thalassemia, while those in red below them on the right-hand side of the figure show some of the deletions that have now been
+
reported in different forms of α -thalassemia. The lines in yellow on the left side of the figure represent some of the deletions that have been reported
0
upstream from the α-globin gene cluster, which, because they remove the major regulatory region, result in the phenotype of α -thalassemia. For a
more detailed list of these deletions and references to those marked in this diagram, see references 45 and 304.
depending on exactly where the crossover occurred. These deletions
142
are designated –α , –α 3.7II , and –α 3.7III , respectively. Other, rarer dele-
3.7I
tions of a single α gene have been observed. 7
Nondeletion α-Thalassemia
Because expression of the α gene is two to three times greater than
2
expression of the α gene, the finding that most of the nondeletion
1
mutants discovered to date affect predominantly α gene expression
2
is not surprising. Presumably this is ascertainment bias because of the
greater phenotypic effect of these lesions. It also is possible that defec-
tive expression of the α gene has come under greater selective pressure.
2
Like the β-thalassemia mutations, α-thalassemia mutations can be
7
classified according to the level of gene expression they affect (see Table
48–5). Several processing mutations have been identified. For example,
a pentanucleotide deletion includes the 5′ splice site of IVS-1 of the
α -globin gene. This mutation involves the invariant GT donor splic-
2
ing sequence and thus completely inactivates the α gene. A second
143
2
Figure 48–11. Mechanisms for production of the common deletion mutant of this type, found commonly in the Middle East, involves the
forms of α -thalassemia. A. Normal α-globin gene cluster showing the poly-A addition signal site (AATAAA→AATAAG) and downregulates
+
homology boxes X, Y, and Z. B. Rightward crossover through the Z the α gene by interfering with 3′ end processing. 144,145
2
bones, giving rise to the 3.7-kb deletion and a chromosome with three A second group of nondeletion α-thalassemias results from muta-
α-globin genes. C. Leftward crossover through the Z boxes, giving rise tions that interfere with translation of mRNA. Several mutations involve
7
to a 4.2-kb deletion and a chromosome containing three α genes. the initiation codon. 146–149 In one case, for example, the initiation codon

Kaushansky_chapter 48_p0725-0758.indd 738 9/18/15 2:57 PM