Abstract
The percentages of the α-chain variant Hb G-Philadelphia (Hb G) or α2 68 Asn→Lysβ2 were evaluated in 84 adult and 18 newborn heterozygotes. These included members of three families who were studied in more detail by nucleic acid hybridization techniques. The adult heterozygotes fell in two categories, one with a higher proportion of Hb G [46.5±1.0% (SD), N=21] and another with lower values (33.9±3.4%, N=63). Among the newborn heterozygotes, two babies fell in the category with the higher proportion of Hb G while 16 babies gave values between 25 and 34%. Studies of α-chain gene organization on the parents of one neonate with a Hb G level of 27% at birth and 37% at 8 months excluded the presence of chromosomes with triplicated α-chain genes which could lead to the α0αG/ααα genotype. Rather, these studies on five Hb G heterozygotes from three families confirmed the linkage between Hb G and a specific type of α-thalassemia-2 associated with the presence of a 16-kbp Bgl II fragment which most probably carries the αG locus since it has been found in 19 Hb G heterozygotes studied to date. The presence of an α-thal-2 heterozygosity and three α-chain genes (α0αG/αα) was confirmed among Hb G heterozygotes with lower proportions of this variant. It is likely that the even lower values found in some newborn could arise through defective assembly of αG-γ dimers. The presence of an α-thal-2 homozygosity and two active α-chain genes, one on each chromosome (α0αG/α0α), was confirmed among heterozygotes with the higher proportion of Hb G. One of each of these categories was present in each of the three families investigated. This type of variability in the number of active α-chain genes due to a heterozygosity or a homozygosity for α-thalassemia-2 explains the trimodality of Hb S percentages among heterozygotes and the atypical hematological or biosynthetic features among patients with β-thalassemia and sickle-cell syndromes.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abraham, E. C., and Huisman, T. H. J. (1977). Differences in affinity of variant β chains for α chains: A possible explanation for the variation in the percentages of β chain variants in heterozygotes. Hemoglobin 1861.
Abraham, E. C., Reese, A., Stallings, M., and Huisman, T. H. J. (1976). Separation of human hemoglobins by DEAE-cellulose chromatography using glycine-KCN-NaCl developers. Hemoglobin 127.
Altay, C., Ringelhann, B., Yawson, C. I., Bruce-Tagoe, A. A., Konotey-Ahulu, F. I. D., James, L., Gravely, M., and Huisman, T. H. J. (1977). Hemoglobin α chain deficiency in black children with variable quantities of hemoglobin Bart's at birth. Pediat. Res. 11147.
Baglioni, C., and Ingram, V. M. (1961). Abnormal human haemoglobins. V. Chemical investigation of haemoglobins A, G, C, and X, from one individual. Biochim. Biophys. Acta 48253.
Baine, R. M., Rucknagel, D. L., Dublin, P. A., Jr., and Adams, J. G., III (1976). Trimodality in the proportion of hemoglobin G-Philadelphia in heterozygotes: Evidence for heterogeneity in the number of human α chain loci. Proc. Natl. Acad. Sci. USA 733633.
Charache, S., Zinkham, W. H., Dickerman, J. D., Brimhall, B., and Dover, G. J. (1977). Hemoglobin SC, SS/G-Philadelphia and SO-Arab Diseases. Diagnostic importance of an integrative analysis of clinical, hematologic, and electrophoretic findings. Am. J. Med. 62439.
Clegg, J. B., Naughton, M. A., and Weatherall, D. J. (1968). Separation of the α and β-chains of human haemoglobin. Nature 21969.
DeSimone J., Kleve, L., Longley, M. A., and Shaeffer, J. (1974). Unbalanced globin chain synthesis in reticulocytes of sickle cell trait individuals with low concentrations of Hemoglobin S. Biochem. Biophys. Res. Comm. 59564.
Dozy, A. M., Kleihauer, E. F., and Huisman, T. H. J. (1968). Studies on the heterogeneity of hemoglobin. XIII. Chromatography of various human and animal hemoglobin types on DEAE-Sephadex. J. Chromatogr. 32723.
Dozy, A. M., Kan, Y. W., Embury, S. H., Mentzer, W. C., Wang, W. C., Lubin, B., Davis, J. R., and Koenig, H. M. (1979). α-Globin gene organisation in Blacks precludes the severe form of α-thalassaemia. Nature 280605.
Embury, S. H., Miller, J. A., Dozy, A. M., Kan, Y. W., Chan, V., and Todd, D. (1980). Two different molecular organizations account for the single α-globin gene of the α-thalassemia-2 genotype. J. Clin. Invest. 661319.
Felice, A. E., and Huisman, T. H. J. (1979). Observations on the calculated contents of variant and normal α chains in adult and fetal erythrocytes. Hemoglobin 3475.
Felice, A., Abraham, E. C., Miller, A., Cope, N., Gravely, M., and Huisman, T. H. J. (1978). Post-translational control of human hemoglobin synthesis; The number of α chain genes and the synthesis of Hb S. In Brewer, G. J., (ed.), The Red Cell Alan R. Liss, New York, pp. 131–154.
Felice, A. E., Webber, B., Miller, A., Mayson, S. M., Harris, H. F., Henson, J. B., Gravely, M. E., and Huisman, T. H. J. (1979). The association of sickle cell anemia with heterozygous and homozygous α-thalassemia-2: In vitro Hb chain synthesis. Am. J. Hematol. 691.
Felice, A. E., Mayson, S. M., Webber, B. B., Miller, A., Gravely, M. E., and Huisman, T. H. J. (1980). Hb S, Hb G-Philadelphia and α-thalassemia-2 in a black family. Pediat Res. 14266.
Felice, A. E., Altay, C., Milner, P. F., and Huisman, T. H. J. (1981a). The occurrence and identification of α-thalassemia-2 among Hb S heterozygotes. Am. J. Clin. Pathol. 7670.
Felice, A. E., Webber, B. B., and Huisman, T. H. J. (1981b). α-Thalassemia and the production of different α chain variants in heterozygotes. Biochem. Genet 19487.
Goosens, M., Dozy, A. M., Embury, S. H., Zachariades, Z., Hadjiminas, M. G., Stamatoyannopoulos, G., and Kan, Y. W. (1980). Triplicated α-globin loci in humans. Proc. Natl. Acad. Sci. USA 77518.
Gross-Bellard, M., Oudet, P., and Chambon, P. (1973). Isolation of high molecular-weight DNA from mammalian cells. Eur. J. Biochem. 3632.
Huisman, T. H. J. (1977). Trimodality in the percentage of β chain variants in heterozygotes: The effect of the number of active Hbα structural loci. Hemoglobin 1349.
Huisman, T. H. J., and Jonxis, J. H. P. (1977). The Hemoglobinopathies. Techniques of Identification Marcel Dekker, New York.
Huisman, T. H. J., Gravely, M. E., Henson, J., Felice, A., Wilson, J. B., Abraham, E. C., Vella, F., and Little, M. W. (1978). Variability in the interaction of β-thalassemia with the α-chain variants Hb G-Philadelphia and Hb Rampa. J. Lab. Clin. Med. 92311.
Huisman, T. H. J., Gardiner, M. B., and Wilson, J. B. (1981). Experiences with the quantitation of human hemoglobin types by high pressure liquid chromatography. In Hanash, S. M., and Brewer, G. J. (eds.), Advances in Hemoglobin Analysis Alan R. Liss, New York, pp. 69–82.
Milner, P. F., and Huisman, T. H. J. (1976). Studies on the proportion and synthesis of haemoglobin G-Philadelphia in red blood cells of heterozygotes, a homozygote, and a heterozygote for both haemoglobin G and α-thalassaemia. Br. J. Haematol. 34207.
Politis-Tsegos, C., Lang, A., Stathopoulou, R., and Lehmann, H. (1976). Is haemoglobin Gα Philadelphia linked to α-thalassaemia? Hum. Genet. 3167.
Pugh, R. P., Monical, T. V., and Minnich, V. (1964). Sickle cell anemia with two adult hemoglobins—Hb S and Hb G-Philadelphia/S. Blood 23206.
Rigby, P. W. J., Dieckman, M., Rhodes, C., and Berg, P. (1977). Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. J. Mol. Biol. 113237.
Rising, J. A., Sautter, R. L., and Spicer, S. J. (1974). Hemoglobin G-Philadelphia/S—A family study of an inherited hybrid hemoglobin. Am. J. Clin. Pathol. 6192.
Sancar, G. B., Tatsis, B., Cedeno, M. M., and Rieder, R. F. (1980). Proportion of hemoglobin G-Philadelphia (α268Asn » Lys β2) in heterozygotes is determined by α-globin gene deletions. Proc. Natl. Acad. Sci. USA 776874.
Sewell, A., Millard, D., and Serjeant, G. R. (1977). The interaction of alpha thalassemia and SS Disease. In Brewer, G. J. (ed.), The Red Cell Alan R. Liss, New York, pp. 93–108.
Shaeffer, J. R., Kingston, R. E., McDonald, M. J., and Bunn, H. F. (1978). Competition of normal β chains and sickle haemoglobin β chains for α chains as post-translation control mechanism. Nature 276631.
Southern, E. M. (1975). Detection of specific sequences among DNA fragments separated by gel electrophoresis. J. Mol. Biol. 98503.
Surrey, S., Ohene-Frempong, K., Rappaport, E., Atwater, J., and Schwartz, E. (1980). Linkage of αG-Philadelphia to α-thalassemia in African Americans. Proc. Natl. Acad. Sci. USA 774885.
Whitney, J. B., III, Martinell, J., Popp, R. A., Russell, L. B., and Anderson, F. W. (1981). Deletions in the α-globin gene complex in α-thalassemic mice. Proc. Natl. Acad. Sci. USA 787644.
Wilson, J. T., Wilson, L. B., DeRiel, J. K., Villa-Komaroff, L., Efstratiadis, A., Forget, B. G., and Weissman, S. M. (1978). Insertion of synthetic copies of human globin genes into bacterial plasmids. Nucleic Acids Res. 5563.
Author information
Authors and Affiliations
Additional information
This research was supported by USPHS Research Grants HLB-05168 and HLB-15158 and by designated research funds of the Veterans Administration. This is Contribution No. 0693 of the Department of Cell and Molecular Biology, Medical College of Georgia, Augusta.
Rights and permissions
About this article
Cite this article
Felice, A.E., Ozdonmez, R., Headlee, M.E. et al. Organization of α-chain genes among Hb G-Philadelphia heterozygotes in association with Hb S, β-thalassemia, and α-thalassemia-2. Biochem Genet 20, 689–701 (1982). https://doi.org/10.1007/BF00483966
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00483966