Heterozygosity for deletion of hypersensitive site 3 in the human locus control region has an unexpected minor effect on red cell phenotype

Abstract

The locus control region (LCR) is a genetic region that regulates the expression of the β-globin locus (HBB locus). This region is composed of several DNase I hypersensitive sites (HSs) in which the regulatory functions of the LCR may reside. To date, some individuals bearing deletions of several HSs or even the complete LCR have been described. Although the globin genes of the HBB locus are intact, most of these patients suffer thalassemia due to the reduced expression of such genes. The LCR and the HSs forming it have been thoroughly studied in different genetic models. However, seemingly contradictory results are often obtained. Here, we describe the first deletion found in humans exclusively affecting the HS3 element of the LCR. The adult carrying this deletion shows very mild hematological modifications, indicating that HS3 deletion does not severely impair the β-gene expression. Our results also reveal limitations of the murine models when studying the native mouse genes for understanding human diseases like thalassemias.