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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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