Non-anemic homozygous beta(o) thalassemia in an African-American family: association of high fetal hemoglobin levels...

We have studied a four-generation (23 subjects) African-American family with beta(o) thalassemia and high fetal hemoglobin (HbF) levels. The beta(o) thalassemia in this family is due to the splicing site mutation, beta IVS2+1G-->A, that leads to aberrant mRNA processing and the absence of beta globin. Two members of this family are homozygous for beta(o) thalassemia and are non-anemic. All family members who are heterozygous for the beta IVS2+1G-->A mutation have elevated HbF, with the exception of two individuals who also have severe alpha-globin chain deficiency. We excluded linkage with the hereditary persistence of fetal hemoglobin loci on chromosomes 6 and X. We also excluded the presence of all previously described determinants in the beta globin gene cluster associated with elevated HbF production. One thalassemia allele is in the Cameroon-like (HS2)/Benin-like beta 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 homozygotes, those erythroid cells that express low to absent levels of gamma globin are selectively destroyed. In contrast, in the heterozygotes, the presence of the normal beta globin allele would ameliorate the globin chain imbalance and thus allow survival of erythroid cells that express the abnormal transcript, leading to a typical beta(o) thalassemia phenotype. Thus, the heterocellular gamma globin expression together with in vivo preferential survival of HbF-containing erythroid cells ameliorates Cooley's anemia in the beta(o) thalassemia homozygotes. It remains to be determined what sequences linked to each thalassemia allele and what trans-acting factors contribute to high HbF levels.