Only one form of this type of thalassemia has been described. It concerns a dele-tion of ~5 kb which likely is the result of an unequal crossover between the Ggamma- and Agamma-globin genes forming a -GAgamma-hybrid gene. The deletion involves the 3' end of the G gamma gene, the 5' end of the Agamma gene, and the intergenic region. Fig. 9 illustrates a gene map listing different restriction sites.
FIG. 9. Comparison of the normal gamma-globin gene region with the gamma gene deletion. A partial restriction map of this region is shown for enzymes BamHI (B), BclI (Bc), BglII (Bg), EcoRI (E), and XbaI (X) (from Ref. 1).
The abnormality is found at low frequencies in different populations (Chinese, Indian, European, Black). It is usually detected through an analysis of DNA from newborn babies with an unusual Ggamma percentage: the normal Ggamma level varies between 65 and 75%, but lower levels are found in heterozygotes for this type of gamma-thal, namely ~40%, because the hybrid -GAgamma-gene expresses as Agamma. Two homozygotes have been discovered (Ref. 2), both had low levels of Hb F at birth (~50% F) consisting of alpha2Agamma2 only. Another anomaly, the -AgammaAgamma-globin gene arrangement (see page 201) resembles the gamma-thal because the heterozygous newborn also has Hb F with low Ggamma values (35-40%); differentiation between the two conditions can be made by gene mapping. The condition is relatively harmless and cannot easily be detected in an adult except through DNA analysis.
One of the Hb F variants, Hb F-Yamaguchi or alpha2gamma2 (75 Ile->Thr; 80 Asp->Asn; 136 Ala) is linked to this type of gamma-thal. Apparently, the GAT->AAT mutation at codon 80 occurred in a -GAgamma-hybrid gene which also carried the common ATA->ACA mutation (Ile-> Thr) at codon 75. This unusual condition [-GAgammaT.X/ Ggamma·Agamma (X = 80 Asp->Asn)] results in the production of 30-35% of the gamma-Yamaguchi chain, which is considerably higher than expected for a normal GgammaAgamma/GgammaAgamma arrangement.
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