Increased γ-globin gene expression in β-thalassemia intermedia patients correlates with a mutation in 3′HS1

Abstract

We report a novel set of genetic markers in the DNasel hypersensitive sites comprising the human β-globin locus chromatin hub (CH), namely HS-111 and 3′HS1. The HS-111 (-21 G>A) and 3HS1 (+179 C>T) transitions form CH haplotypes, which occur at different frequencies in β-thalassemia intermedia and major patients and normal (nonthalassemic) individuals. We also show that the 3′HS1 (+179 C>T) variation results in a GATA-1 binding site and correlates with increased fetal hemoglobin production in β-thalassemia intermedia patients. In contrast, the HS-111 (+126 G>A) transition, found in three normal chromosomes, is simply a rare polymorphism. We conclude that the CH haplotypes are useful genetic determinants for β-thalassemia major and intermedia patients, while the 3′HS1 (+179 C>T) mutation may have functional consequences in γ-globin genes expression. © 2007 Wiley-Liss, Inc.