Non-anemic homozygous beta degrees thalassemia in an african-american family: Association of high fetal hemoglobin levels with beta thalassemia alleles

We have studied a four-generation (23 subjects) African-American family wit h beta degrees thalassemia and high fetal hemoglobin (HbF) levels. The beta degrees thalassemia in this family is due to the splicing site mutation, b eta IVS2+1G-->A, that leads to aberrant mRNA processing and the absence of beta globin. Two members of this family are homozygous for beta degrees tha lassemia and are non-anemic. All family members who are heterozygous for th e beta IVS2+1G-->A mutation have elevated HbF, with the exception of two in dividuals who also have severe alpha -globin chain deficiency. We excluded linkage with the hereditary persistence of fetal hemoglobin loci on chromos omes 6 and X. We also excluded the presence of all previously described det erminants in the beta globin gene cluster associated with elevated HbF prod uction. One thalassemia allele is in the Cameroon-like (HS2)/Benin-like bet a globin gene cluster haplotype, and the other is in the Senegal-like (HS2) /Benin-like beta globin gene cluster haplotype. We speculate that in the ho mozygotes, those erythroid cells that express low to absent levels of gamma globin are selectively destroyed. In contrast, in the heterozygotes, the p resence of the normal beta globin allele would ameliorate the globin chain imbalance and thus allow survival of erythroid cells that express the abnor mal transcript, leading to a typical beta degrees thalassemia phenotype. Th us, the heterocellular gamma globin expression together with in vivo prefer ential survival of HbF-containing erythroid cells ameliorates Cooley's anem ia in the beta degrees thalassemia homozygotes. It remains to be determined what sequences linked to each thalassemia allele and what trans-acting fac tors contribute to high HbF levels. Am. J. Hematol. 68:43-50, 2001. (C) 200 1 Wiley-Liss, Inc.