960
APPENDIX VII
FIGURK VII-5
R estriction enzym e m ap o f a-globin gene cluster and som e of the deletions (indicated as dark lines).
HbA
2
(>3.5%) and, in some mutations, by HbF and nor-
mal serum iron studies.
a-Thalassemia:
The a-globin gene cluster is found
in chromosome 16 and each chromosome contains two
a
genes (a
2
and
a
|). Thus each individual has four copies
of
a
gene. The genes are present in the order: 5r-f2-
l-i/ra
2
-i/fal-a
2
-ai-
0 1
-
3
' (Figure VII-5). The t
p
genes
(pseudogenes) and 01 gene are nonfunctional. The
rp
genes are thought to be relics of the past evolutionary gene
mutations. The
0
1
gene does not yield a viable globin pro-
tein product and its function is not known. a-Thalassemia
is probably the most common genetic defect, and its preva-
lence correlates with geographic areas of malaria inci-
dence. The clinical manifestations of a-thalassemia de-
pends on the number of genes affected. Gene deletions
are the most common defect, and point mutations account
only for about 5% of a-thalassemia.
a-Thalassemia silent carrier
(aa/a-): This genotype
is caused by a single a 2-globin gene defect, primarily
due to —a
3
7
or —a
4 2
deletion. The superscript indi-
cates the length of deletion in kilobases of DNA. Both
deletions are caused by unequal crossover points occur-
ring at different locations. The reciprocal product of un-
equal crossover yields a triplicated a-globin gene. Indi-
viduals who have inherited single a-gene defect do not
exhibit any hematological or clinical manifestations and
the relative proportion of hemoglobins A, A2, and F are
normal.
a-Thalassemia-2
(a-/a-): Inheritance of two single-
gene defects gives rise to clinically significant microcy-
tosis, and the relative proportions of hemoglobins A, A2,
and F are normal.
a-Thalassemia-1
(—/aa): Two-gene deletions on the
same chromosome are characterized by microcytic ane-
mia. Different deletions have been observed. Southeast
Asian (—SEA) and Filipino (—Fl1) are examples of two-gene
deletions occurring in the designated geographic areas.
Deletion of a regulatory element (HS-40, see Chapter 28)
also results in thalassemia syndrome.
Hemoglobin H disease:
Compound heterozygosity for
a-thalassemia
- 1
and a-thalassemia
- 2
deletions give rise
to hemoglobin H (HbH) disease. These individuals exhibit
hemolytic, microcytic anemia, which is not life threaten-
ing. HbH(/34) inclusions are identified by supravital stain-
ing with brillian cresyl blue (discussed earlier) and as fast-
moving hemoglobin in cellulose acetate, alkaline pH 8.4
electrophoresis technique (Figure VII-1).
Hemoglobin Bart’s hydrops fetails:
This occurs due
to inheritance of two a-thalassemia
- 1
allels and the off-
spring does not have any functional a genes. This con-
dition is incompatible with life and results in stillborn
or critically ill fetus with hydrops fetalis. Hemoglobin
