There are several alpha chain variants which result from mutations in the alpha2alpha1 hybrid gene of the chromosome with the 3.7 kb deletion or in the only remaining alpha1-globin gene of the chromosome with the 4.2 kb deletion. These alpha-thal-2 linked abnormal Hbs usually occur in the heterozygote at significantly higher levels [~30-35% in -alpha(X)/alphaalpha] than in heterozygotes with four alpha-globin genes [20-25% in alpha(X)alpha/alphaalpha or alphaalpha(X)/alphaalpha]. Examples are:
(1). The GAG->AAG mutation occurred in a Surinam family on a chromosome with the 3.7 kb (type I) deletion. The quantity of the alpha-Chad chain averaged 31.5% in its carriers [alpha(Chad)(-3.7 kb)/alphaalpha], and 43% in the two carriers with an additional alpha-thal-2 homozygosity [-alpha(Chad)(-3.7 kb)/ -alpha(-3.7 kb)]. These quantities are considerably higher than those reported for families from Chad, China, and Japan; the low levels of 14.5-24% Hb in these persons suggest a mutation on a chromosome with two alpha-globin genes.
Senno et al (2) report levels of ~32% in a family from Northern Italy; the carriers were also heterozygous for the -3.7 kb deletion and the two abnormalities were linked. Studies of families from different parts in the USA, Australia, and Austria have indicated lower levels (15.3-20.4% in eight individuals of six families). The mutation (GAC->CAC) was found in the alpha2-globin gene and none of the individuals had an alpha-thal-2 heterozygosity (unpublished data).
(3-5). This variant in the Black population is associated with the 3.7 kb deletion; its quantity in heterozygotes[-alpha(X)/alphaalpha] varies between 30 and 35%, and the alpha-thal-2 in homozygotes [-alpha(X)/-alpha] between 40 and 45%. The mutation involves an AAC->AAG change at codon 68. Other individuals, Caucasians of Italian origin, have a lesser amount (~25% Hb G) and four alpha-globin genes; the mutation concerns an AAC->AAA change at codon 68 of the alpha2 gene [alpha(X)alpha/alphaalpha]. Fig. 23 shows the distribution of the quantities of Hb G in numerous heterozygotes and in nine heterozygotes with a homozygosity for the 3.7 kb alpha-thal-2 deletion.
FIG. 23. The percentages of Hb G-Philadelphia in heterozygotes with four, three, or two alpha-globin genes. Data obtained in the author's laboratory by DEAE-cellulose or cation exchange HPL chromatography.
(6,7). This variant is due to a GAC->CAC mutation at codon 74 of the alpha1-globin gene of an alpha-thal-2 chromosome with the 4.2 kb deletion. The quantities in heterozygotes [-alpha(X)/alphaalpha] from China, Hong Kong, Canada (five families) ranged from 27.4-34.9% (unpublished data). Patients with Hb Q-Hb H disease [-alpha(X)/- -] only produce Hb Q, Hb H, and Hb Bart's.
(8). This rare variant, found in a few Chinese families, is due to a GAC->GCC mutation at codon 75 of the alpha1-globin gene on the chromosome with the 4.2 kb deletion [-alpha(X)/alphaalpha]. The heterozygote has ~37% Hb Duan.
(9). This variant was present in one homozygote and three heterozygotes of a family from the Congo. The mutation (AAC-> AAG) was found on the alpha2alpha1 hybrid gene of a chromosome with the 3.7 kb deletion [-alpha(X)/alphaalpha]. The heterozygote had 32-35% of alpha(X) and the homozygote had 100% alpha(X) [-alpha(X)/-alpha(X)]. There are also older reports (10-13) of lower quantities (~24%) in simple heterozygotes.
(14,15). This CGG->CAG mutation at codon 92 has been found to be associated with the 3.7 kb deletion [-alpha(X)/alphaalpha]. The quantity in four such persons varied between 29.2 and 33.8% (unpublished data).
(16-18). The GCC->GAC mutation occurs on a chromosome with the 3.7 kb (type III) deletion. The quantity of alpha(X) varies between 45 and 50% in the heterozygote [presumably -alpha(X)/-alpha] and 100% in the homozygote [-alpha(X)/-alpha(X)].
|1.||Codrington, J.F., Codrington, F.A., Wisse, J.H., Wilson, J.B., Webber, B.B., Wong, S.C., and Huisman, T.H.J.: Hemoglobin, 13:543, 1989.|
|2.||Senno, L., Bernardi, F., Marchetti, G., Perrotta, C., Conconi, F., Vullo, C., Salsini, G., Cristofori, G., Cappellozza, G., Bellinello, F., Bedendo, B., and Mercuriati, M.: Eur. J. Biochem., 111:125, 1980.|
|3.||Milner, P.F. and Huisman, T.H.J.: Br. J. Haematol., 34:207, 1976.|
|4.||Safaya, S. and Rieder, R.F.: J. Biol. Chem., 263:4328, 1988.|
|5.||Molchanova, T.P., Pobedimskaya, D.D., Ye, Z., and Huisman, T.H.J.: Am. J. Hematol., 45:345, 1994.|
|6.||Lorkin, P.A., Charlesworth, D., Lehmann, H., Rahbar, S., Tuchinda, S., and Lie Injo, L.E.: Br. J. Haematol., 19:117, 1970.|
|7.||Higgs, D.R., Hunt, D.M., Drysdale, H.C., Clegg, J.B., Pressley, L., and Weatherall, D.J.: Br. J. Haematol., 46:387, 1980.|
|8.||Liang, S., Tang, Z., Su, S., Lung, Q., Liang, R., Fei, Y.J., Kutlar, F., Wilson, J.B., Webber, B.B., Hu, H., and Huisman, T.H.J.: Hemoglobin, 12:13, 1988.|
|9.||Costa, F.F., Sonati, M.F., and Zago, M.A.: Hum. Genet., 86:319, 1991.|
|10.||Dherte, P., Vandepitte, J., Ager, J.A.M., and Lehmann, H.: Br. Med. J., ii:282, 1959.|
|11.||Schneider, R.G. and Haggard, M.E.: Br. Med. J., ii:285, 1959.|
|12.||Van Ros, G., Beale, D., and Lehmann, H.: Br. Med. J., 4:92, 1968.|
|13.||North, M.L., Darbre, P.D., Lehmann, H., and Juif, J.G.: Acta Haematol., 53:56, 1975.|
|14.||Lambridis, A.J., Ramsay, M., and Jenkins, T.: Br. J. Haematol., 63:363, 1986.|
|15.||Molchanova, T.P., Pobedimskaya, D.D., and Huisman, T.H.J.: Br. J. Haematol., 88:300, 1994.|
|16.||Abramson, R.K., Rucknagel, D.L., and Shreffler, D.C.: Science, 169:194, 1970.|
|17.||Beavan, G.H., Hornabrook, R.W., Fox, R.H., and Huehns, E.R.: Nature, 235:46, 1972.|
|18.||Hill, A.V.S., Bowden, D.K., Trent, R.J., Higgs, D.R., Oppenheimer, S.J., Thein, S.L., Mickleson, K.N.P., Weatherall, D.J., and Clegg, J.B.: Am. J. Hum. Genet., 37:571, 1985.|