section 28.3
inherited Disorders of Hemoglobin Structure and Synthesis
669
populations because the HbS that increases resistance to
malaria caused by
Plasmodium falciparum,
which was,
until recently, endemic in those areas. A similar expla-
nation has been advanced for the high frequencies of
/
8
-thalassemia and single a-locus genotypes in the same
regions. The biological basis of resistance to malaria has
been established in laboratory experiments. As schizonts
of
P. falciparum
grow in erythrocytes, they lower the intra-
cellular pH and generate hydrogen peroxide. The lower pH
promotes sickling and the hydrogen peroxide damages cell
membranes of thalassemic erythrocytes. In both cases, the
erythrocyte membranes become more permeable to potas-
sium ions; the resulting decrease in intracellular potassium
kills the parasites.
The mutation in HbS replaces glutamic acid (a polar
amino acid) by valine (a nonpolar residue) at position
6
of the
/3
chains. The solubilities of oxy- and deoxy-HbA
and oxy-HbS are similar, being about 50 times that of
deoxy-HbS. Upon deoxygenation, HbS precipitates, form-
ing long, rigid, polymeric strands that distort and stiffen
the red cells. The very high concentration of hemoglobin
in the erythrocyte (340 mg/mL), giving an average inter-
molecular distance of about 1 nm (10 A), minimizes the
time necessary for precipitations to occur. Dilution of HbS,
as in sickle cell trait (HbS/HbA heterozygotes), reduces
the concentration below the point at which sickling readily
occurs. Similarly, the mildness of homozygous HbS dis-
ease in populations such as those of eastern Saudi Arabia
and Orissa, India is attributed to an accompanying eleva-
tion of HbF, which reduces the effective concentration of
HbS tetramers.
Other abnormal hemoglobins can interact with HbS and
alter the course of the disease. The most common is HbC,
which has a lysine in place of glutamic acid, also at /36.
The gene has a frequency second only to that of HbS
in black Americans and in some black African popula-
tions. Persons heterozygotic for HbC are asymptomatic,
but homozygotic individuals have a mild hemolytic ane-
mia with splenomegaly. Because of its insolubility, crys-
tals of HbC can sometimes be seen in peripheral blood
smears from homozygous individuals. As a result of the
coincidental distribution of the genes for HbS and HbC,
heterozygotes for both hemoglobins are not uncommon.
HbSC disease has a severity intermediate between that
seen in persons homozygotic for HbS and those homozy-
gotic for HbC. Unlike HbA, HbC copolymerizes with HbS.
In contrast, replacement of the
/36
glutamic acid by ala-
nine (HbG-Makassar) or deletion of
/36
(Hb Leiden) re-
sults in hemoglobin that neither precipitates nor interacts
with HbS. Hb San Jose (Glu —►
Gly at residue
/31)
is a
harmless variant.
Individuals heterozygous for HbS and HbO Arab or
HbD Los Angeles have a hemolytic anemia of a severity
intermediate between that of HbSC disease and sickle
cell anemia. Certain «-chain variants (e.g., Hb Memphis),
when present in HbS homozygotes, can ameliorate the
clinical course of the disease. The severity of HbS-/3-
thalassemia depends on whether the thalassemia is
f3°
or
/3+
and, if it is
(3
', on how much normal
/3
chain is syn-
thesized. Severity also depends on the HbF concentration.
A patient with heterozygosity for both HbS
and
Hb Quebec-chori exhibited clinical symptoms sugges-
tive of sickle cell disease. Hb Quebec-chori, an elec-
trophoretically silent variant at acid and alkaline pH (see
Appendix VII) (/187 Thr -»• lie), polymerizes with HbS
with the stabilization of the polymer under hypoxic con-
ditions leading to sickling of red blood cells. Thus, Hb
Quebec-chori provides an example of a hemoglobin that
has the potential to polymerize with HbS and causing
sickle cell disease in a sickle cell trait condition which
is otherwise benign by itself.
Determination of the structure of crystalline HbS has
shown that in the
f3
subunits of oxy-HbA and oxy-HbS, a
“hydrophobic pocket” between helices E and F is closed;
this opens in the deoxy form. In HbA, the residues at the
surfaces of the globin subunits are hydrophilic (polar) and
do not interact with this pocket. In HbS, however, the /16
valine is hydrophobic and fits into the hydrophobic pocket
(formed by leucine and phenylalanine at /885 and /
888
) of
an adjacent
(3
chain to form a stable structure. Since each
/3
subunit in deoxy-HbS has an “acceptor” hydrophobic
pocket and a “donor” valine, linear aggregates form
(Figure 28-15).
Understanding of the sickling process and of the struc-
ture of the HbS polymer provides a rational basis for ways
of correcting the molecular defect. Thus, dilution of the
HbS in the red cells, blockage of the interaction of the
/36
valine with the hydrophobic pocket, and decrease of
F IG U R E 2 8 -1 5
Structure of hemoglobin S (HbS) polymer. The valine at the /16 position of
the deoxy-HbS fits into the hydrophobic pocket formed by leucine and
phenylalanine at
[3
85 and /188 of an adjacent /1 chain. Since each
f3
chain
has an “acceptor” pocket and a “donor” valine, the HbS polymer has a
double-stranded, half-staggered structure. [Reproduced with permission
from S. Charache, Advances in the understanding of sickle cell anemia.
H osp. P ract.
21(2), 173 (1986). J. E. Zupko, illustrator.]
