Hemoglobinopathies are clinical conditions that result from mutations thatchange the sequences of bases in DNA of the genes for globins If the bases in the DNA are changed even by a single one, then a modified protein may be produced (or no protein at all). The consequences can be negligible, severe or fatal. Mutations are inherited and, if the disease is not fatal, then the disease symptoms will be inherited too. The severity of the disease may depend on whether one or both copies of the gene in question carry the mutation, in other words, whether the individual is homozygous or a heterozygote. The mutations involved in hemoglobinopathies include point mutations, the largest group, that substitute one amino acid residue for another, insertions or deletion of one or more residues, drastic changes caused by frameshift mutations (Margin Note 13.6) and alterations in the lengths of the polypeptide chains by mutations that produce or destroy stop codons.
In normal adult humans, there are two α - and one β-globin genes, coding for polypeptides of 141 and 146 amino acid residues respectively, which go to form HbA, α 2 β 2. In a diploid cell there are actually four α and two β genes. Each of these genes has two introns (Margin Note 13.7). The α genes are located on chromosome 16 and the β genes on chromosome 11. If there is a mutation, it may have been inherited from one or both parents giving a heterozygous or homozygous condition respectively. A mutation in an α gene tends to have less serious consequences than one in a β gene because there may still be nonmutated copies of the α gene present. Nevertheless, even small changes in the structure of the Hb protein can sometimes result in disastrous clinical effects. Over 750 Hb mutations are known. They usually only affect one type of subunit because there are separate genes for the α - and the β-globins (Table13.2).
Originally, many of the different mutant Hbs were identified by their mobilities in electrophoresis (Figure 13.19) and peptide mapping but now, of course, the DNA can be analyzed directly. A major technical advance has been the ability to make DNA probes that are specific for α -or β-chains. This means it is possible to identify which mRNAs are being produced and identify any mutations present. Thus the different clinical variants can be understood at the molecular level. For example, in so-called ‘hemoglobin H disease’ it has been shown that there is only one of the four possible α -globin genes present and functioning, so that only 25% of the normal amount of α -chain mRNA is produced. The mutation causing this situation is a deletion not a point mutation.
The majority of mutations are harmless and therefore do not produce a hemoglobinopathy because they do not cause disease. For example, mutations distant from the heme binding cleft, or from the regions of subunit contact may have little effect on the properties of the Hb. However, mutations may change the shape of the globin subunit(s), the binding of the heme groups or even prevent globin synthesis, all with severe clinical consequences. To function properly, the four subunits in the Hb molecule must fit together tightly but still produce a molecule that is flexible. The regions of contact have been conserved in evolution and are essential for normal functions, such as the cooperative binding of O2 (Figure 13.7). Thus mutations can upset the delicate balance of interactions between the amino acid side chains with several consequences. The molecule may dissociate upon deoxygenation and, in some cases, the monomers may precipitate in the erythrocytes reducing O2 affinity. Microscopically, the denatured and precipitated Hb can be seen as Heinz bodies (and Figure 13.20). A deletion of one or more amino acid residues or substitution mutations can produce this effect, as in Hb Leiden and Hb Philly respectively. There may also be cell membrane damage, with intravascular hemolysis, anemia, reticulocytosis and splenomegaly as consequences. In other cases, a small change in the regions that bind the heme groups may make the pockets slightly less hydrophobic so that it does not bind appropriately, and again, the denatured Hb can precipitate to form Heinz bodies. Thus only two of the four subunits may have heme groups. In other cases, the change in the pocket allows the iron to become oxidized to the Fe3+(III) state (methemoglobin), which will not bind O2. The resulting condition is referred to as methemoglobinemia and patients become cyanosed because they lack oxygen.
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