The number of nondeletional alpha-thal determinants is steadily increasing. At present (April 1997) as many as 32 different types have been reported. All but a few are extremely rare; others are found at low frequencies in various populations such as Hb Constant Spring (Hb CS; alpha142, TAA->CAA); initiation codon mutation ATG->ACG; the 5 nts deletion at the IVS-I donor site of alpha2, and one of the poly A mutations (AATAAA->AATAAG). All 32 alleles are described on pages 240 through 263; it might be helpful to review the sequences of the alpha2- and alpha1-globin genes which are presented in Figs. 18 and 19.
Table XXI lists the 32 alleles according to the changes in functional properties caused by the mutations. Fourteen mutations (including the frameshifts) result in the (assumed) synthesis of (often hyper)unstable Hbs; the absence of any functional alpha chain synthesis by the alpha-globin gene with the mutation results in an alpha-thal-2 type of condition. Nine mutations occur in the alpha2-globin gene; three in the alpha1-globin gene, and one in the hybrid alpha2alpha1 gene of a chromosome with the -alpha(3.7) deletion, while for one this information is not available.
Many mutations and some frameshifts affect the translation of mRNA; most are changes in the initiation codon [two in alpha2, one in alpha1, two in the alpha2alpha1 hybrid gene due to the -alpha(3.7) deletion] and the terminating codon (all of the alpha2-globin gene), while three can be found in the IVS-I sequence. Also interesting are the changes in the poly A site of the alpha2-globin gene: two mutations and two deletions affect the addition of poly A because of changes in the AATAAA sequence. Not listed are a few variants that were reported some time ago but have not been characterized.
The first of the five presently known terminating codon mutations was elucidated in 1971; Clegg et al in a beautifully executed protein analytical study demonstrated that the minor Hb Constant Spring, found in a Chinese family from Jamaica, had an extended alpha chain. They identified and sequenced this carboxy terminus which was extended by 31 amino acid residues (1). Clegg et al similarly identified a second terminating variant, Hb Icaria (2). Since then three additional variants have been detected and identified, mainly by DNA analysis. Carriers of all five have the clinical phenotype of mild alpha-thal-2, while homozygotes have a distinct, but mild, anemia with microcytosis and hypochromia. Combination with deletional alpha-thal-2 and alpha-thal-1 determinants have been found (mainly Hb Constant Spring with the SEA type of alpha-thal-1); their phenotype is one of rather severe Hb H disease with a high Hb H level and often a transfusion dependency.
One can expect a total of nine mutations of the stop codon TAA (codon 142). As shown in Fig. 20, five have been discovered, two (TAG; TGA) will cause no change because both also function as a stop codon, while one (TAA->TTA for leucine) has not been discovered.
FIG. 18. Sequence-Reading Chart for the Alpha2-Globin Gene
FIG. 19. Sequence-Reading Chart for the Alpha1-Globin Gene
FIG. 20. The nine mutations of the TAA stop codon 142 (from Ref. 5).
|1.||Liebhaber, S.A.: Hemoglobin, 13:685, 1989.|
|2.||Higgs, D.R.: in The Haemoglobinopathies, edited by D.R. Higgs and D.J. Weatherall, Bailliere's Clinical Haematology, Vol. 6, page 117, W.B. Saunders Company, London, 1993.|
|3.||Clegg, J.B., Weatherall, D.J., and Milner, P.F.: Nature, 234:337, 1971.|
|4.||Clegg, J.B., Weatherall, D.J., Contopolou-Griva, I., Caroutsos, K., Poungouras, P., and Tsevrenis, H.: Nature, 251:245, 1974.|
|5.||Merritt, D., Jones, R.T., Head, C., Thibodeau, S.N., Fairbanks, V.F., Steinberg, M.H., Coleman, M.B., and Rodgers, G.P.: Hemoglobin, in press, 1997.|