Loss of Major DNase I Hypersensitive Sites in Duplicated β-globin Gene Cluster Incompletely Silences HBB Gene Expression

Abstract

We report an infant with sickle cell disease phenotype by biochemical analysis whose β-globin gene (HBB) sequencing showed sickle cell mutation (HBB^S ) heterozygosity. The proband has a unique head-to-tail duplication of the β-globin gene cluster having wild-type (HBB^A ) and HBB^S alleles inherited from her father; constituting her HBB^S /HBB^S -HBB^A genotype. Further analyses revealed that proband's duplicated β-globin gene cluster (∼650 kb) encompassing HBB^A does not include the immediate upstream locus control region (LCR) or 3' DNase I hypersensitivity (HS) element. The LCR interacts with β-globin gene cluster involving long range DNA interactions mediated by various transcription factors to drive the regulation of globin genes expression. However, a low level of HBB^A transcript was clearly detected by digital PCR. In this patient, the observed transcription from the duplicated, distally displaced HBB^A cluster demonstrates that the loss of LCR and flanking 3'HS sites do not lead to complete silencing of HBB transcription.

Keywords: HBB duplication; globin genes; regulation; sickle cell disease.