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.