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Loss of Major DNase I Hypersensitive Sites in Duplicated β-globin Gene Cluster Incompletely Silences HBB Gene Expression. | LitMetric
We report an infant with sickle cell disease phenotype by biochemical analysis whose β-globin gene (HBB) sequencing showed sickle cell mutation (HBB ) heterozygosity. The proband has a unique head-to-tail duplication of the β-globin gene cluster having wild-type (HBB ) and HBB alleles inherited from her father; constituting her HBB /HBB -HBB genotype. Further analyses revealed that proband's duplicated β-globin gene cluster (∼650 kb) encompassing HBB 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 transcript was clearly detected by digital PCR. In this patient, the observed transcription from the duplicated, distally displaced HBB cluster demonstrates that the loss of LCR and flanking 3'HS sites do not lead to complete silencing of HBB transcription.
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