Although these hybrid Hbs have been listed in a previously published syllabus which provides details about the Hb variants (1) a description is included here because all three are associated with a thalassemic condition. The deletion is about 7.4 kb long and involves the 3' end of the delta-globin gene, the 5' end of the beta-globin gene, and the intergenic region. The loss of this large segment of DNA likely arose during crossover between misaligned chromosomes. The synthesis of the resulting hybrid chain (deltabeta) is considerably less than that of the beta chain and only slightly higher than that of the delta chain, resulting in a thalassemic condition. The crossover areas have recently been determined in greater detail; earlier information was based on data from protein analysis only, but results from sequencing analysis of the amplified deltabeta hybrid genes provided the information which is listed in Fig. 15. The data for Hb Lepore-WB are from Refs. 3 and 4, for Hb Lepore-Balt from Refs. 3 and 5, and for Hb Lepore-Holl. From Ref. 6.
Hb Lepore-WB was discovered in 1958 (7). It is found worldwide but is most common in Italy, Spain, and the countries from the Balkan Peninsula. The heterozygote is only mildly anemic (Hb 11-13 g/dl) but with a significant hypochromia and microcytosis (MCV 70-75-fl; MCH 20-24 pg). The Hb A2 level is 2.0-2.5%; the delta chain production by the one delta chain of the normal chromosome is increased to a value seen in beta-thal heterozygotes. Homozygotes are rather severely affected. Nearly 20 subjects have been described with a Hb S-Hb Lepore compound heterozygosity (see Ref. 2); these persons have only a moderate-to-mild anemia. The combination with Hb E is much more severe and such a compound heterozygote requires regular blood transfusions. The Hb Lepore-WB condition has also been observed in combination with different beta-thal alleles (IVS-I-110, G->A; codon 39, C->T; IVS-I-5, G->A; IVS-I-6, T->C). The clinical condition of such a patient is primarily determined by the type of beta-thal; for instance, patients with Hb Lepore/IVS-I-110 (G->A) or Hb Lepore/codon 8 (-AA) have a complete dependency on blood transfusions (9,10).
Hb Lepore-Balt was discovered in 1969 (11). It is quite often found in Central Portugal, Italy, and Brazil (3,5,10-12). A compound heterozygote with a deltabeta-thal suffered from a severe type of beta-thal (12). The Hb Lepore-Balt heterozygote usually has slightly higher levels of Hb F (3-5%) as compared to those seen in Hb Lepore-WB heterozygotes (1-3%); otherwise, no differences in hematological values are seen (13).
Hb Lepore-Holl was discovered in 1962 (14) in a few families in Papua New Guinea, Papua, and has also been found in Bangladesh (6). Clinical and hematological information about carriers of this variant are limited.
FIG. 15. The locations of the areas of crossover between the delta- and beta-globin genes leading to the formation of the deltabeta hybrid genes of Hb Lepore-Washington-Boston (WB), Hb Lepore-Baltimore (Balt), Hb Lepore-Hollandia (Holl), and the anti-Lepore betadelta gene of Hb P-Nilotic (from Ref. 2).
|1.||Huisman, T.H.J., Carver, M.F.H., and Efremov, G.D.: A Syllabus of Human Hemoglobin Variants (1996), The Sickle Cell Anemia Foundation, Augusta, GA, 1996.|
|2.||Huisman, T.H.J.: Hemoglobin, 21:249, 1997.|
|3.||Ribeiro, M.L., Cunha, E., Gonçalves, P., Martin Núñez, G., Fernandez Galan, M.A., Tamagnini, G.P., Smetanina, N.S., Gu, L-H., and Huisman, T.H.J.: Hum. Genet., 99:669, 1997.|
|4.||Fioretti, G., De Angioletti, M., Masciangelo, F., Lacerra, G., Scaralio, A., de Bonis, C., Pagano, L., Guarino, E., De Rosa, L., Salvati, F., and Carestia, C.: Am. J. Hum. Genet., 50:781, 1992.|
|5.||Miranda, S.R.P., Figueiredo, M.S., Kerbauy, J., Grotto, H.Z.W., Saad, S.T.O., and Costa, F.F.: Acta Haematol., 91:7, 1994.|
|6.||Waye, J.S., Eng, B., Patterson, M., Chui, D.H.K., Chang, L.S., Cogionis, B., Poon, A.O., and Olivieri, N.F.: Am. J. Hematol., 47:262, 1994.|
|7.||Gerald, P.S. and Diamond, L.K.: Blood, 13:835, 1958.|
|8.||Efremov, G.D.: Hemoglobin, 2:197, 1978.|
|9.||Efremov, D.G., Efremov, G.D., Zisovski, N., Stojanovski, N., Kutlar, F., Diaz-Chico, J.C., Kutlar, A., Yang, K.G., Stoming, T.A., and Huisman, T.H.J.: Br. J. Haematol., 68:351, 1988.|
|10.||Bozkurt, G., Baysal, E., Gu, L-H., and Huisman, T.H.J.: Hemoglobin, 18:247, 1994.|
|11.||Ostertag, W. and Smith, E.W.: Eur. J. Biochem., 10:371, 1969.|
|12.||Efremov, G.D., Rudicic, R., Niazi, G.A., Hunter, E., Jr., Huisman, T.H.J., and Schroeder, W.A.: Scand. J. Haematol., 16:81, 1976.|
|13.||Ribeiro, M.L., Cunha, E., Gonçalves, P., Martin Núñez, G., Fernandez Galan, M.A., Tamagnini, G.P., Smetanina, N.S., Gu, L-H., and Huisman, T.H.J.: Hum. Genet., 99:669, 1997.|
|14.||Barnabas, J. and Muller, C.J.: Nature, 194:931, 1962.|