section 28.3
Inherited Disorders of Hemoglobin Structure and Synthesis
/1-gene complex consists
of s, Gy, Ar, S,
and at least
one pseudo-/! gene. Clustering of the «-like and /1-like
genes is consistent with the hypothesis that members of
each family arose by duplication of, and divergence from,
a parent a or yd gene. The order of the genes in each group,
from 5' to 3', is the same as that of their expression during
ontogeny. The order on the chromosome may be impor-
tant for regulation of globin gene expression, as appears
to be the case for the immunoglobulin heavy-chain genes
(Chapter 35). The dynamics of globin gene expression and
hemoglobin synthesis involve the participation of many
genes. These include cis-acting promoter elements (e.g.,
TATA and CCAAT boxes, duplicated CACCC motifs), en-
hancer elements, and the presence of the genes that are
absolutely required for expression. The gene cluster that
is required for expression of /f-globin-likc genes is located
in the locus control region (LCR) marked by five DNase-
hypersensitive sites (HSs), and an analogous site in the
«-globin gene cluster is known as HS-40 (Figure 28-12).
Transcription of the /1-gene cluster begins with the forma-
tion of the transcription complex on the promoter, which
involves the interaction of the locus control gene with an
individual hemoglobin gene along with trans-acting tran-
scription factors and RNA polymerase II.
Although the a-like and /3-like polypeptides contain
141 and 146 residues, respectively, the corresponding
genes are considerably longer than required, since there
are two introns within each globin gene. In contrast to the
/3-gene cluster located on chromosome 16, the a-globin
genes are duplicated on chromosome 11 (Figure 28-12).
Thus, in a diploid cell, four
genes are present. Introns
are transcribed with exons, but they are removed (“spliced
out”) from the RNA before it leaves the nucleus. Although
mutations in introns are generally under less “selection
pressure” (have a lesser effect on fitness of the organism)
than mutations in exons, mutations or deletions in introns
may affect normal RNA splicing, causing thalassemia syn-
dromes. The major steps involved in the synthesis of the
/1-globin polypeptide chain are shown in Figure 28-13, to-
gether with the sites in the /
-globin gene that are involved
in the synthesis.
The degree of relatedness of the globin genes can be
estimated from the number of amino acid differences in
the peptides or the number of base differences in the DNA.
The thalassemias are a heterogeneous group of hypo-
chromic, microcytic anemias caused by unbalanced syn-
thesis of globin chains. In Southeast Asia, the Philippines,
China, the Hawaiian Islands, and the Mediterranean coun-
tries, thalassemia syndromes are relatively common and
constitute a significant public health problem. Worldwide,
they are probably the most common hereditary diseases.
The clinical severity of these disorders ranges from mild
or totally asymptomatic forms to severe anemias, caus-
ing death
in utero.
Presentation depends on the specific
globin genes, acquired conditions that modify the expres-
sion of these genes, race, and inheritance of genes for
structural hemoglobin variants (most often HbS or HbC).
Anemia and other characteristic hematological abnormal-
ities are due to ineffective erythropoiesis and to precip-
itation of the excess free globin chains within the red
cells. Ineffective erythropoiesis causes the appearance of
hypochromic red cells, with a clear center and darker rim
containing the hemoglobin (target cells). The precipitates
form inclusions, called Heinz bodies, which are removed
(“pitted out”) by the spleen with consequent membrane
damage. The resulting cells, called poikilocytes, have
abnormal shapes and a shortened life span. Sequestration
Transcription Signals
1. R N A polym erase promotor; this is the binding site
for R N A polymerase II.
2. 5 ' End of the R N A transcript and base to which the
7-m ethyl guanylate-5'-diphosphate cap is attached.
3. Initiation site for translation of m ature m essage into
protein, i.e., the codon A U G for initiator methionyl
tRN A. This am ino acid is rem oved following translation.
4. Coding sequence for exon 1 (am ino add s 1 -3 0 ). In the
m RN A, the 3 ' end of this sequence (base 143) will be
linked to the 5 ' end of exon 2 (base 274).
5. Splice "donor" for intron 1. C leavage of the bond
between this and the preceding base m arks the beginning
of the R N A sequence to be excised.
6. Intron 1. Sequences of the recognition sites within
the intron for splicing are not yet known for certain.
7. Splice "acceptor" for intron 1. C leavage of the bond
between this and the next base m arks the end of the RN A
sequence to be exdsed.
8. Coding sequence forexon 2 (amino acids 3 1 -1 0 4 ). In th e
m RN A, bases 2 74 and 143 will be linked, as will bases
495 and 1346.
9. Splice "donor” for exdsion of intron 2.
10. Intron 2.
11. Splice "acceptor' for excision of intron 2.
12. Coding sequence for exon 3 (am ino acids 105 -1 4 6 ).
13. Translation termination codon read by th e termination
factors causing the ribosomes and nascent polypeptide
chain to be released. For the B-globin gene,
itisU A A .
14. T he poly(A) tail is attached to the 3'e n d of this base.
Transcription probably continues beyond this point, but
the primary transcript is processed by removal of all RN A
3 ' (downstream ) from this base.
(base pairs)
- 5 0 to —1
5 1 -5 3
5 4 -1 4 3
1 4 4 -2 7 3
2 7 4 -4 9 5
4 9 6 -1 3 4 5
134 6-1 471
147 2-1474
F IG U R E 2 8 -1 3
Summary of regulation of transcription in human /j-globin genes. Base
pairs in DNA are numbered from the transcription initiation site. Bases
downstream (in the direction of 5 ' —
r- 3') have positive numbers, and bases
upstream have negative numbers. E = Exon; I = intron; A„, represents the
polyadenylate “tail” of length
(Courtesy of Dr. R. Condit.)
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