revised April 17, 2002
Hemoglobin is produced by genes that control the expression of the hemoglobin
protein. Defects in these genes can produce abnormal hemoglobins and anemia,
which are conditions termed "hemoglobinopathies". Abnormal hemoglobins appear
in one of three basic circumstances:
- Structural defects in the hemoglobin molecule. Alterations in the gene for one
of the two hemoglobin subunit chains, alpha (a) or beta (b), are called mutations. Often, mutations change a single amino acid building block in the subunit. Most
commonly the change is innocuous, perturbing neither the structure nor function of
the hemoglobin molecule. Occasionally, alteration of a single amino acid dramatically disturbs the behavior
of the hemoglobin molecule and produces a disease state. Sickle hemoglobin exemplifies
- Diminished production of one of the two subunits of the hemoglobin molecule.
Mutations that produce this condition are termed "thalassemias." Equal numbers
of hemoglobin alpha and beta chains are necessary for normal function. Hemoglobin
chain imbalance damages and destroys red cells thereby producing anemia. Although there is
a dearth of the affected hemoglobin
subunit, with most thalassemias the few subunits synthesized are structurally normal.
- Abnormal associations of otherwise normal subunits. A single subunit of
the alpha chain (from the a-globin locus) and a single subunit
from the b-globin locus combine to produce a normal hemoglobin
dimer. With severe a-thalassemia, the b-globin
subunits begin to associate into groups of four (tetramers) due to the paucity of
potential a-chain partners. These tetramers of b-globin
subunits are functionally inactive and do not transport oxygen. No comparable tetramers
of alpha globin subunits form with severe beta-thalassemia. Alpha subunits are rapidly
degraded in the absence of a partner from the beta-globin gene cluster (gamma, delta,
beta globin subunits).
Types of hemoglobins
There are hundreds of hemoglobin variants that involve involve genes both from the
alpha and beta gene clusters. The list below touches on some of the
more common and important hemoglobin variants.
- Hemoglobin A. This is the designation for the normal hemoglobin that exists
after birth. Hemoglobin A is a tetramer with two alpha chains and two beta chains
- Hemoglobin A2. This is a minor component of the hemoglobin found in red cells
after birth and consists of two alpha chains and two delta chains (a2d2).
Hemoglobin A2 generally comprises less than 3% of the total red cell hemoglobin.
- Hemoglobin F. Hemoglobin F is the predominant hemoglobin during fetal development.
The molecule is a tetramer of two alpha chains and two gamma chains (a2g2).
The genes for hemoglobin F and hemoglobin A are closely related, existing in the same gene cluster on chromosome 11. Hemoglobin
F production falls dramatically after birth, although some people continue
to produce small amounts of hemoglobin F for their entire lives.
Clinically Significant Variant Hemoglobins
- Hemoglobin S. This the predominant hemoglobin in people with sickle cell disease.
The alpha chain is normal. The disease-producing mutation exists in the beta chain,
giving the molecule the structure, a2bS2.
People who have one sickle mutant gene and one normal beta gene have sickle cell
trait which is benign.
- Hemoglobin C. Hemoglobin C results from a mutation in the beta globin gene and
is the predominant hemoglobin found in people with
hemoglobin C disease (a2bC2).
Hemoglobin C disease is relatively benign, producing a mild hemolytic anemia and
splenomegaly. Hemoglobin C trait is benign.
- Hemoglobin E. This variant results from a mutation in the hemoglobin beta chain.
People with hemoglobin E disease have a mild hemolytic anemia and mild splenomegaly.
Hemoglobin E trait is benign. Hemoglobin E is extremely common in S.E. Asia and in
some areas equals hemoglobin A in frequency.
- Hemoglobin Constant Spring.
Hemoglobin Constant Spring is a variant in which a mutation in the alpha globin gene
produces an alpha globin chain that is abnormally long.
The quantity of hemoglobin in the cells is low for
two reasons. First, the messenger RNA for hemoglobin Constant Spring is
unstable. Some is degraded prior to protein synthesis. Second, the Constant
Spring alpha chain protein is itself unstable. The result is a thalassemic
phenotype. (The designation Constant Spring derives from the isolation
of the hemoglobin variant in a family of ethnic Chinese background from
the Constant Spring district of Jamaica.)
- Hemoglobin H. Hemoglobin H is a tetramer composed of four beta globin chains. Hemoglobin H occurs only with extreme limitation of alpha chain
availability. Hemoglobin H forms in people with three-gene alpha thalassemia as well
as in people with the combination of two-gene deletion alpha thalassemia and hemoglobin Constant Spring.
- Hemoglobin Barts.
Hemoglobin Barts develops in fetuses with four-gene deletion alpha thalassemia. During
embryonic development, the episilon gene of the alpha globin gene locus combines
with genes from the beta globin locus to form functional hemoglobin molecules. The episolon gene turns off at
about 12 weeks, and normally the alpha gene takes over. With four-gene deletion alpha
thalassemia no alpha chain is produced. The gamma chains produced during fetal development
combine to form gamma chain tetramers. These molecules transport oxygen poorly. Most
individuals with four-gene deletion thalassemia and consequent hemoglobin Barts die
in utero (hydrops fetalis). The abnormal hemoglobin seen during fetal development
in individuals with four-gene deletion alpha thalassemia was characterized at St.
Bartholomew's Hospital in London. The hospital has the fond sobriquet, St. Barts,
and the hemoglobin was named "hemoglobin Barts."
Compound Heterozygous Conditions
Hemoglobin is made of two subunits derived from genes in the alpha gene cluster on chromosome 16 and
two subunits derived from genes in the beta gene cluster on chromosome 11. Occasionally
someone inherits two different variant genes from the alpha globin gene cluster or two different
variant genes from the beta globin gene cluster (a gene for hemoglobin S and one
for hemoglobin C, for instance). This condition is called "compound heterozygous".
The nature of two genes inherited determines whether a clinically significant disease
The compound heterozyous states tends to consist of common groupings (e.g., hemoglobin
SC), due to the geographic
clustering of hemoglobin variants around the world.
- Hemoglobin SC disease. Patients with hemoglobin SC disease inherit a gene for hemoglobin
S from one parent, and a gene for hemoglobin C from the other. Hemoglobin
C interacts with hemoglobin S to produce
some of the abnormalities seen in patients with sickle cell disease. On
average, patients with hemoglobin SC disease have milder symptoms than
do those with sickle cell disease. This is only an average, however. Some
people with hemoglobin SC disease have a condition equal in severity to that of any patient with sickle cell disease. A number other syndromes
exist that involve a hemoglobin S compound heterozyous state. They are less common than hemoglobin SC disease, however.
Ironically, hemoglobin SC disease is often a much more severe condition than
is homozygous hemoglobin C disease. The expression of a single hemoglobin S gene
normally produces no problem (i.e., sickle cell trait). The hemoglobin C molecule
disturbs the red cell metabolism only slightly. However, the disturbance is enough
to allow the deleterious effects of the hemoglobin S to be manifested.
- Sickle/beta-thalassemia. In this condition, the patient has inherited a gene for hemoglobin S from
one parent and a gene for beta-thalassemia from the other. The severity
of the condition is determined to a large extent by the quantity of normal
hemoglobin produced by the beta-thalassemia gene. (Thalassemia genes produce
normal hemoglobin, but in variably reduced amounts). If the gene produces
no normal hemoglobin, b0-thalassemia,
the condition is virtually identical to sickle cell disease. Some patients
have a gene that produces a small amount of normal hemoglobin, called
The severity of the condition is dampened when significant quantities of
normal hemoglobin are produced by the b+-thalassemia
gene. Sickle/beta-thalassemia is the most common sickle syndrome seen in
people of Mediterranean descent (Italian, Greek, Turkish). Beta-thalassemia
is quite common in this region, and the sickle cell gene occurs in some
sections of these countries. Hemoglobin electrophoresis of blood from a
patient with sickle/b0-thalassemia shows no hemoglobin A. Patients
with sickle/b+-thalassemia have an amount
of hemoglobin A that depends of the level of function of the b+-thalassemia
- Hemoglobin E/beta-thalassemia. The combination of hemoglobin E and beta-thalassemia
produces a condition more severe than is seen with either hemoglobin E trait or beta-thalassemia trait.
The disorder manifests as a moderately severe thalassemia that falls into the category
thalassemia intermedia. Hemoglobin E/beta-thalassemia is most common in people
of S.E. Asian background.
- Alpha thalassemia/Hemoglobin Constant Spring. This syndrome is a compound heterozygous
state of the alpha globin gene cluster.
The alpha globin gene cluster on one of the two chromosomes 16 has both alpha globin
genes deleted. On the other chromosome 16, the alpha1 gene has the Constant Spring
mutation. The compound heterozygous condition produces a severe shortage of alpha
globin chains. The excess beta chains associate into tetramers to form hemoglobin
The thalassemias are a group of disorders in which the normal hemoglobin
protein is produced in lower amounts than usual. The genes are defective
in the amount of hemoglobin they produce, but that which they produce
is normal. The thalassemias
are a complex group of disorders because of the genetics of hemoglobin
production and the structure of the hemoglobin molecule.
Bunn HF, Forget B. Hemoglobin: Molecular, Genetic and Clinical Aspects.
Philadelphia, PA, Saunders, p. 453. 1986