Page 756 - Williams Hematology ( PDFDrive )

730 Part VI: The Erythrocyte Chapter 48: The Thalassemias: Disorders of Globin Synthesis 731

TABLE 48–2. Molecular Pathology of the β-Thalassemias this distribution pattern, only approximately 20 alleles account for the
majority of all β-thalassemia determinants (see Fig. 48–1).
β - or β -Thalassemia
+
0
Transcription Gene Deletions
At least 17 different deletions affecting only the β genes have been
Deletions
described. With one exception, the deletions are rare and appear to be
Insertions isolated, single events. The 619-bp deletion at the 3′ end of the β gene
48
Promoter is more common, but even that is restricted to the Sind and Gujarati
populations of Pakistan and India, where it accounts for approxi-
5′-UTR
48
mately 50 percent of β-thalassemia alleles. The Indian 619-bp deletion
Processing of mRNA removes the 3′ end of the β gene but leaves the 5′ end intact. Many of
Junctional the other deletions remove the 5′ end of the gene and leave the δ gene
intact. 49–53 Homozygotes for these deletions have β -thalassemia. Het-
0
Consensus splicing sequences
erozygotes for the Indian deletion have increased hemoglobin A and
2
Cryptic splice sites in introns F levels identical to those seen in heterozygotes for the other common
Cryptic splice sites in exons forms of β-thalassemia. Heterozygotes for the other deletions all have
unusually high hemoglobin A levels. Increased δ-chain production
7
Poly (A) addition site 2
results from increased δ-gene transcription in cis to the deletion, pos-
Translation sibly as a result of reduced competition from the deleted 5′ β gene for
Initiation transcription factors.
Nonsense Other Transcriptional Mutations
Frameshift Several different base substitutions involve the conserved sequences
7
Posttranslational stability upstream from the β-globin gene. In every case, the phenotype is
+
β -thalassemia, although considerable variability exists in the clinical
Unstable β-chain variants
severity associated with different mutations of this type. Several muta-
Normal hemoglobin A β-thalassemia tions, at positions –88 and –87 relative to the mRNA CAP site, for
2
β-Thalassemia and δ-thalassemia, cis or trans example, 54,55 are close to the CCAAT box, whereas others lie within the
TATA box homology. 56–59
“Silent” β-thalassemia
Some mutations upstream from the β-globin gene are associated
Some promoter mutations with even more subtle alterations in phenotype. For example, a C→T
CAP +1, CAP +3, etc. substitution at position –101, which involves one of the upstream
promoter elements, is associated with “silent” β-thalassemia, that is, a
5′ UTR completely normal (“silent”) phenotype that can be identified only by
Some splice mutations its interaction with more severe forms of β-thalassemia in compound
60
Dominant β-thalassemia heterozygotes. A single example of an A→C substitution at the CAP
site (+1) was described in an Asian Indian who, despite being homozy-
Mainly point mutations or rearrangements in exon 3 gous for the mutation, appeared to have the phenotype of the β-thalas-
Other unstable variants semia trait. 61
Upstream regulatory mutations confirm the importance of the role
UTR, untranslated region. of conserved sequences in this region as regulators of the transcription
note: A full list of mutations is given in Refs. 7 and 45. of the β-globin genes and provide the basis for some of the mildest
forms of β-thalassemia, particularly those in African populations, and
for some varieties of “silent” β-thalassemia.
of the β-globin gene and nondeletional mutations that may affect the
transcription, processing, or translation of β-globin messenger (Table RNA-Processing Mutations
48–2 and Fig. 48–5). Each major population group has a different set One surprise about β-thalassemia has been the remarkable diversity of
of β-thalassemia mutations, usually consisting of two or three muta- the single-base mutations that can interfere with the intranuclear pro-
tions forming the bulk and large numbers of rare mutations. Because of cessing of mRNA.

Deletions Figure 48–5. Classes of mutations
that underlie β-thalassemia. C, CAP site;
FS, frameshift; I, initiation site; NS, non-
sense mutation; POLY A, polyA addition
site mutation; PR, promoter; SPL, splicing
1 IVS-1 2 IVS-2 3 mutation. For a complete list see ref. 304.

PR CI FS SPL SPL FS SPL SPL FS POLY A
NS NS NS
Point mutations 100 bp

Kaushansky_chapter 48_p0725-0758.indd 731 9/18/15 2:57 PM