Molecular pathology

The a0-thalassaemias result from deletions of both a-globin genes. There are many different-sized deletions; however, one is particularly common in South-East Asia and another occurs mainly in Mediterranean populations (Figure 6.11). a0-Thalassaemia may also result from deletions about 40 kb upstream from the a-globin gene cluster, which involve the HS40 region.

The molecular basis of the a+-thalassaemias is more complicated. In some cases, they result from deletions that remove one of the linked pairs of a-globin genes, leaving the other one intact (-a/aa). In others, both a-globin genes are intact but one of them has a mutation that either partially or completely inactivates it (aTa/aa).

Each a-gene lies within a boundary of homology approximately 4 kb long. These regions were generated by a duplication, and subsequently were subdivided, presumably by insertions and deletions, to give three homologous subsegments that are

Figure 6.11 The a-globin gene cluster deletions that underlie a0-thalassaemia (from Weatherall and Clegg 2001 with permission).

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inter-ÇHVR ya2 a2





Figure 6.12 The molecular mechanisms that underlie the deletion forms of a+-thalassaemia. (a) Normal cluster showing X, Y and Z homology boxes; (b) 3.7-kb deletion; (c) 4.2-kb deletion.

designated X, Y and Z (Figure 6.12). The duplicated Z boxes are 3.7 kb apart and the X boxes are 4.2 kb apart. Misalignment and reciprocal crossover between these segments at meiosis produces a chromosome with either single (- a) or triplicated (aaa) a-globin genes. If the crossover occurs between the Z boxes, 3.7 kb of DNA is lost, an event that is described as a right-

ward deletion, written as - a3 7. A crossover between the two X boxes deletes 4.2 kb, the leftward deletion, - a42. There are at least three different subtypes of the 3.7-kb deletion.

In the non-deletion forms of a-thalassaemia, the a-globin genes are intact but one of them is inactivated by a mutation, many of which are similar to those that cause P-thalassaemia.

One particularly common form, found in South-East Asia, results from a single-base change in the chain termination codon UAA, which changes to CAA. The latter is the codeword for the amino acid glutamine. Hence, when the ribosomes reach this point, instead of the chain terminating, mRNA that is not normally transcribed is read through until another stop codon is reached. Thus, an elongated a-globin chain is produced, which is synthesized at a reduced rate. The resulting variant is called Hb Constant Spring. Because the termination codon can change in other ways, there is a family of variants of this kind.

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