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The molecular basis of alpha thalassemias frequent occurrence of dys functional alpha loci among non asians with hemo globin h disease


, : The molecular basis of alpha thalassemias frequent occurrence of dys functional alpha loci among non asians with hemo globin h disease. Cell 17(1): 33-42

Study of Asians previously indicated that deletion of .alpha.-globin structural genes is the predominant lesion in .alpha.-thalassemias and that Hb H disease occurs when 3 of 4 normal .alpha. loci per cell are deleted. To test the generality of this model, Hb H disease DNA of both Asian and non-Asian origin were analyzed by restriction endonuclease mapping using the technique of Southern (1975). Whereas in normal DNA, .alpha. sequences are present in a single EcoRI fragment of cellular DNA approximately 22.5 kb [kilobase] long, fragments of 22.5, 20 and 2.6 kb were found in various Hb H disease DNA. The 20 kb EcoRl fragment alone, in which a single .alpha.-globin structural locus resides, was found in Asian Hb H disease DNA. This is consistent with the deletion model of .alpha.-thalassemia. Of 8 non-Asian Hb H disease DNA, 7 displayed a more complex molecular composition. The fragment patterns observed were 22.5 kg alone, 22.5 plus 2.6 kg, 20 plus kb 2.6 kb and 20 kb alone. Non-Asian Hb H disease DNA contained 1, 2 or 3 .alpha. loci per cell in contrast to the 1 locus predicted by the simple deletion model of .alpha.-thalassemia. The existence of defective .alpha. loci in certain individuals with .alpha.-thalassemia, particularly outside the Asian population, is a possibility. Restriction mapping of the 20 kb EcoRl fragment found in Asian and some non-Asian Hb H disease DNA demonstrated a striking similarity in the placement of restriction sites about the single .alpha. gene compared with sites about the 2 genes in the 22.5 kg EcoRl fragment seen in normal DNA. These data are consistent with origin of the 20 kb fragment from the 22.5 kb normal EcoRl fragment by either unequal crossing-over or a deletion event. The molecular heterogeneity and frequent occurrence of defective .alpha. loci in non-Asian Hb H disease DNA described here may explain, in part, the clinical heterogeneity of .alpha.-thalassemias and the absence of the homozygous deletion state (hydrops fetalis) in non-Asians. Further study of cellular DNA fragments containing the defective .alpha. loci identified in this work may indicate the types of specific mutations responsible for abnormal globin gene espression and complement similar studies on abnormal .beta. genes in .beta.-thalassemias.

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Related references

Orkin, S.H.; Old, J.; Lazarus, H.; Altay, C.; Gurgey, A.; Weatherall, D.J.; Nathan, D.G., 1979: The molecular basis of alpha-thalassemias: frequent occurrence of dysfunctional alpha loci among non-Asians with Hb H disease. Study of Asians has previously indicated that deletion of alpha-globin structural genes is the predominant lesion in alpha-thalassemias and that Hb H disease occurs when three of four normal alpha loci per cell are deleted. To test the generality...

Kan Y.W.; Dozy A.M.; Varmus H.E.; Taylor J.M.; Holland J.P.; Lie Injo L.E.; Ganesan J.; Todd D., 1975: Deletion of alpha globin genes in hemo globin h disease demonstrates multiple alpha globin structural loci. Nature (London) 255(5505): 255-256

Dublin P.A.Jr; Cates M.; Rucknagel D.L., 1974: Bi modality of the proportion of hemo globin g alpha philadelphia suggesting heterogeneity in the number of hemo globin alpha chain loci. Pediatric Research 8(4): 388

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Sumida I., 1975: Studies of abnormal hemo globins in western japan frequency of visible hemo globin variants and chemical characterization of hemo globin sawara alpha 2 6 alanine beta 2 and hemo globin mugino hemo globin ferrara alpha 2 4 glycine beta 2. Japanese Journal of Human Genetics 19(4): 343-364

Stocklen Z., 1972: Multiple alpha chain loci for human hemo globins hemo globin j buda and hemo globin g pest. Nature (london)332): 47-50

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Lie-Injo, L.E.; Dozy, A.M.; Kan, Y.W.; Lopes, M.; Todd, D., 1979: The alpha globin gene adjacent to the gene for hemo globin q alpha 74 asparagine replaced by histidine is deleted but not that adjacent to the gene for hemo globin g alpha 30 glutamic acid replaced by glycine 0.75 of the alpha globin genes are deleted in hemo globin q alpha thalassemia. Two Chinese patients with HbQ-.alpha.2 74 Asp .fwdarw. His .beta.2-.alpha.-thalassemia, 1 HbQ-.alpha.2 74 or 75 Asp .fwdarw. His .beta.2 carrier, and 1 HbG-.alpha.2 30 Glu .fwdarw. Gln .beta.2 carrier were studied to determine the number of .alpha...

Steinberg, M.H.; Coleman, M.B.; Adams, J.G.; Hartmann, R.C.; Saba, H.; Anagnou, N.P., 1986: A new gene deletion in the alpha-like globin gene cluster as the molecular basis for the rare alpha-thalassemia-1(--/alpha alpha) in blacks: HbH disease in sickle cell trait. A novel deletion of at least 26 kilobase of DNA, including both alpha-globin genes, the psi alpha- and psi zeta-globin genes, but sparing the functional zeta-gene was found in a 10-year-old black boy with HbH disease and sickle cell trait. This pa...

Wickramasinghe S.N.; Hughes M.; Fucharoen S.; Wasi P., 1984: The fate of excess beta globin chains within erythropoietic cells in alpha thalassemia 2 trait alpha thalassemia 1 trait hemo globin h disease and hemo globin q h disease an electron microscope study. EM studies were performed on bone marrow cells from individuals with various .alpha.-thalassemia syndromes. Globin chain precipitates were rarely found in the erythropoietic cells of a subject with .alpha.-thalassemia 2 trait. By contrast, such pr...