revised April 17, 2002

(Hemoglobin Disorders)

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:
  1. 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 this phenomenon.

  2. 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.

  3. 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.
Normal Hemoglobins

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

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 state develops. 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.


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 (generally) is normal. The thalassemias are a complex group of disorders because of the genetics of hemoglobin production and the structure of the hemoglobin molecule.
Suggested Reading:
Bunn HF, Forget B. Hemoglobin: Molecular, Genetic and Clinical Aspects. Philadelphia, PA, Saunders, p. 453. 1986