section 28.3
Inherited Disorders of Hemoglobin Structure and Synthesis
663
TABLE 28-4
Characteristics of the ß -Thalassemia Syndromes *
Hemoglobin Pattern
Molecular Defect
Type
Severity
Ai
a
2
F
mRNA
Genes
Homozygous States
ß
+-Thalassemia
Cooley’s anemia
(thalassemia
major)
+
+
/3-mRNAmarkedly
reduced
/
3
-genes present
/3°-Thalassemia
Cooley’s anemia
0
+
+
Absent or
nonfunctional
/3-mRNA
/
3
-genes present
S°ß
“-Thalassemia
Milder disease
(thalassemia
intermedia)
0
0
100
%
Absence of/3-
andS-mRNA
Deleted /3- and
5-genes
HB Lepore
Cooley’s anemia
0
0
(and 25%Hb
Lepore)
75%
Absence of normal
/3- and
6
-mRNA
Normal/3-and
5-genes absent,
5/3-fusion gene
present
Heterozygous States
ß
+-Thalassemia
Mild disease
(/3-thalassemia
trait or/3-
thalassemia
minor)
+
(usually not
more than
6.5%)
= or
slightly+
Deficiency of
/3-mRNA
/
3
-genes present
/j°-Thalassemia
Mild disease
+
(usually not
more than
6.5%)
= or
slightly +
Deficiency or
nonfunctional
/3-mRNA
/
3
-genes present
8ß
-Thalassemia
Mild disease
5-20%
Deficiency of/3-
and 5-mRNA
Deletion of/3- and 5-
genes on one
chromosome
Hb Lepore
Mild disease
i
(and 5-15%
Hb Lepore)
+
Deficiency of
normal /3- and
5-mRNA
5/3-fusion gene on
one chromosome;
other chromosome
normal
*+ means that the fraction of the indicated hemoglobin in the erythrocyte is variably increased relative to that of a normal individual; - means de-
creased; = means normal fraction; and
0
means that the hemoglobin is absent.
chains is homologous with that of 5-globin, and the
C-terminal sequence is homologous with that of /3-globin.
The fusion gene arose from nonhomologous crossing over
between the 5 gene on one chromosome and the /3 gene
on the other. The products are a chromosome with a
S-p
fusion gene but no normal /3 or 5 loci, and a chromo-
some with normal
p-
and 5-globin genes and a
P-S
fusion
gene. Homozygotes for the <5-/1 (Lepore) chromosome will
have a
S'
°/3°-thalassemia, while homozygotes for the /3-5
(anti-Lepore) chromosome will be clinically normal, have
normal
p~
and 5-chain synthesis, and produce a /3-5 fu-
sion chain. Three 5-/3 fusion genes (hemoglobins Lepore-
Hollandia, Lepore-Boston, and Lepore-Baltimore) and
three anti-Lepore genes (hemoglobins Miyada, P-Congo,
and P-Nilotic), which differ in the crossover site, have
been identified. Because of the high degree of homology
between the 5 and
p
genes (96%), it is difficult to pin-
point the exact crossover site. HPFH and 5-/3-thalassemia
are also thought to result from nonhomologous crossovers
within the /3-gene family.
In
homozygotes
for Hb
Lepore
and
Gy-Ay-5-/3-
thalassemia, the deletion does not extend beyond the 5'
end of the 5 gene, and the Gy and Ay loci are only weakly
expressed. In three deletions identified in homozygotes
for HPFH, DNA upstream from the 5' end of the 5 locus
is deleted together with some or all of the 5 and
p
loci.
