G y
« y
m .
/8- gene family
n I________ a i_____ a n __________________________3 1
H b L E P O R E
W < & / 3 )° th a l
(8/3)° thal
G y * y H P F H
G y Ay H P F H
H b K E N Y A
G y Ay (8)3)° thal
Gy (8/3)° thal
Gy(S/3 )° thal
(y S 0 !°th a l
/3° *hal
FIGURE 28-14
Chromosomal organization of the human
-globin gene family and deletions that cause thalassemia (thal). In the /3-gene
family, the exons are shown as dark boxes and the introns as open boxes. The various deletions are shown by horizontal
bars under the /9-gene family. Cross-hatched regions indicate uncertainty in the termination points of the deletion.
Arrows indicate unmapped end points of the deletion. [Reproduced with permission from R. A. Spritz and B. G. Forget,
The thalassemias: molecular mechanisms of human genetic disease.
A m . J. H um . G enet.
35, 336 (1983). © 1983 by the
University of Chicago Press.]
Presumably, sequences somewhere in that region repress
expression of the /genes; removal of these sequences al-
lows unrestrained expression of the / loci. If the dele-
tion extends too close to the
locus, however, expres-
sion of the Gy gene is reduced, producing the more se-
vere phenotype seen in Gy-i5-/l-thalassemia. Finally, in
/ - /
-thalassemia, the
locus and both / loci are deleted,
while the
gene is normal; yet there is no synthesis of any
of the /1-like globins. The reason for the nonexpression
of this normal
locus is unknown. Thus, these disorders
hint at the presence of regulatory information within the /
gene complex. It may eventually be possible to activate the
/genes to produce HPFH-like states and reduce the mor-
bidity associated with /
-thalassemias and with mutations
affecting the function or stability of the /
-globin chain.
In normal adults, the small amount of HbF present is
distributed nonuniformly among the erythrocytes. The dis-
tribution pattern was established by selective extraction of
HbA from erythrocytes in a peripheral blood smear. The
more poorly soluble HbF left behind stains pink with eosin.
In most persons who have HPFH, all erythrocytes contain
some HbF.
The term
refers to hemoglobin dis-
orders caused by normal synthesis of qualitatively abnor-
mal globin chains. Transcription and translation of mutant
genes usually proceed at a normal rate, but the products
denature rapidly or function abnormally.
A selected list of mutant hemoglobins is given in
Table 28-5. The most common mutations are the single-
amino-acid substitutions caused by one nucleotide change
in a globin gene. The table also lists several deletion muta-
tions and one nonsense mutation. Globin chains that con-
tain two mutations are extremely rare and appear to have
resulted from a second mutation in a common mutant (usu-
ally HbS or HbC).
Molecular Pathology
The effect of a mutation on the structure and function
of hemoglobin is determined by the effects of the amino
acid change. Many residues in hemoglobin have been con-
served during evolution, probably because they are es-
sential for normal hemoglobin function. The most critical
regions for normal structure and function are the heme
contacts and oq/l, and
contacts. Substitutions near
the heme group can cause weak or absent heme binding, re-
sulting in loss of the heme group from the affected subunits
(Hb Sydney, Hb Hammersmith). They can also stabilize
the iron as Fe3+ and prevent reversible oxygen binding
(as in hemoglobin M). The heme group is also less tightly
bound in methemoglobin than normal hemoglobin.
Substitutions in amino acids involved in subunit con-
tacts can have several effects. In Hb Philly, a Tyr —> Phe
change in the at
a \ ft
, interface eliminates a hydrogen bond
needed to stabilize deoxyhemoglobin (T-state) and leads
to dissociation into monomers, which precipitate. This
dissociation decreases cooperativity and increases oxygen
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