title: 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 (HBBS) heterozygosity. The proband has a unique head-to-tail duplication of the β-globin gene cluster having wild-type (HBBA) and HBBSalleles inherited from her father; constituting her HBBS/HBBS-HBBAgenotype. Further analyses revealed that proband's duplicated β-globin gene cluster (∼650 kb) encompassing HBBAdoes 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 HBBAtranscript was clearly detected by digital PCR. In this patient, the observed transcription from the duplicated, distally displaced HBBAcluster demonstrates that the loss of LCR and flanking 3'HS sites do not lead to complete silencing of HBB transcription.
authors: Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah.|Division of Hematology, Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, Utah.|Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah.
authors: N Scott
authors: NS
authors: Reading
authors: Molecular Haematology, Division of Cancer Studies, King's College London Faculty of Life Sciences & Medicine, London, UK.
authors: Claire
authors: C
authors: Shooter
authors: Division of Hematology, Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, Utah.
authors: Jihyun
authors: J
authors: Song
authors: Center for Cancer and Blood Disorders, Nemours/El Dupont Hospital for Children, Wilmington, Delaware.
authors: Robin
authors: R
authors: Miller
authors: Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah.|Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah.
authors: Archana
authors: A
authors: Agarwal
authors: Division of Hematology, Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, Utah.|Department of Cell and Developmental Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors: Lucie
authors: L
authors: Lanikova
authors: Molecular Haematology, Division of Cancer Studies, King's College London Faculty of Life Sciences & Medicine, London, UK.|Department of Molecular Pathology, Viapath at King's College Hospital NHS Foundation Trust, London, UK.
authors: Barnaby
authors: B
authors: Clark
authors: Molecular Haematology, Division of Cancer Studies, King's College London Faculty of Life Sciences & Medicine, London, UK.|National Heart, Lung and Blood Institute, Sickle Cell Branch, National Institutes of Health, Bethesda, Maryland.
authors: Swee Lay
authors: SL
authors: Thein
authors: Department of Biology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. vladimir.divoky@upol.cz.|Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. vladimir.divoky@upol.cz.
authors: Vladimir
authors: V
authors: Divoky
authors: Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah. josef.prchal@hsc.utah.edu.|Division of Hematology, Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, Utah. josef.prchal@hsc.utah.edu.|Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah. josef.prchal@hsc.utah.edu.
authors: Josef T
authors: JT
authors: Prchal
mesh_terms: D024509:3' Flanking Region; D000755:Anemia, Sickle Cell / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D020131:Genes, Duplicate; D006801:Humans; D007223:Infant; D019901:Locus Control Region; D009154:Mutation; D014158:Transcription, Genetic; D055544:beta-Globins / Q000235:genetics*
chemical_list: D055544:beta-Globins
keywords: HBB duplication; globin genes; regulation; sickle cell disease