Thalassemias

Variant Hemoglobins - Hemoglobin variants (see here) arise from missense mutations. By contrast, if one or more of the chains of hemoglobin are produced in insufficient amounts, a pathological condition called thalassemia arises. Thalassemia can arise in the following ways:

> 1. One or more of the genes coding for hemoglobin chains is deleted.

> 2. One or more of the genes coding for hemoglobin chains may have undergone a nonsense mutation that produces a shortened chain or a frameshift mutation that produces a nonfunctional chain (see Figure 7.21b and c).

> 3. A mutation may have occurred outside the coding regions, leading to a block in transcription or to improper processing of the pre-mRNA, so the protein is not produced or is not functional.

In case 1 or 2, the gene produces no functional protein. In case 3, limited transcription and translation of the correct polypeptide sequence may occur.

Classes - Two major classes of thalassemias involving loss or misfunction of genes for the adult and chains:

> -Thalassemia - In individuals where the globin gene is lost or cannot be expressed, no chains are made. These individuals are dependent upon continued production of the fetal chains to make a functional hemoglobin, 2 2. Such individuals may produce chains well into childhood, but they usually die before reaching maturity.

> Much less serious is the heterozygous state, in which one gene is still functioning. Milder thalassemias (called 1) are known in which transcription or processing of the genes are partially inhibited, reducing the amount of globin synthesized.

> -Thalassemias - Thalassemias involving the chain are more complicated. Two copies of the gene (1 and 2) are next to each other on human chromosome 16. Their sequences differ by only one amino acid, and one can replace the other in the assembled hemoglobin tetramer. An individual can have 4, 3, 2, 1, or 0 copies of an gene. Only if three or more genes are nonfunctional are serious effects observed. Individuals with only one gene are anemic, because their total hemoglobin production is low. The low level of hemoglobin is partially compensated for by formation of 4 tetramers (hemoglobin H) and 4 tetramers (hemoglobin Bart's). These tetramers can bind and carry oxygen, but they do not exhibit the allosteric transition (they remain always in the R state), nor do they exhibit a Bohr effect. As a result, the unloading of oxygen to tissues is inefficient. If all four gene copies are missing, individuals with this condition are inevitably stillborn. They can form only 4 hemoglobin and, because the supply of chains falls near birth (Figure 7.22), not enough hemoglobin is available to support the near-term fetus.

Because there are two copies of the gene but only one of the gene, the most deleterious mutations in mammalian hemoglobins usually occur in the chains. This phenomenon may suggest a functional role for gene duplication. That is, if two or more copies of a gene are present, the species is somewhat protected from the harmful effects of mutations.

See also: Hemoglobin Variants, Globin Gene Expression in Development, Evolution of Myoglobin/Hemoglobin Proteins, Mechanisms of Protein Mutation, Hemoglobin

INTERNET LINKS:

> 1. Thalassemia Overview

> 2. Sickle Cell Disease

> 3. Hemoglobin Overview

> 4. Globin Gene Server