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Loss of Major DNase I Hypersensitive Sites in Duplicated β-globin Gene Cluster Incompletely Silences HBB Gene Expression
NS. Reading, C. Shooter, J. Song, R. Miller, A. Agarwal, L. Lanikova, B. Clark, SL. Thein, V. Divoky, JT. Prchal,
Language English Country United States
Document type Case Reports, Journal Article, Research Support, Non-U.S. Gov't
PubMed
27492747
DOI
10.1002/humu.23061
Knihovny.cz E-resources
- MeSH
- 3' Flanking Region MeSH
- beta-Globins genetics MeSH
- Genes, Duplicate * MeSH
- Transcription, Genetic MeSH
- Infant MeSH
- Humans MeSH
- Mutation MeSH
- Locus Control Region MeSH
- Anemia, Sickle Cell genetics MeSH
- Gene Silencing MeSH
- Check Tag
- Infant MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
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 HBBS alleles inherited from her father; constituting her HBBS /HBBS -HBBA genotype. Further analyses revealed that proband's duplicated β-globin gene cluster (∼650 kb) encompassing HBBA 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 HBBA transcript was clearly detected by digital PCR. In this patient, the observed transcription from the duplicated, distally displaced HBBA cluster demonstrates that the loss of LCR and flanking 3'HS sites do not lead to complete silencing of HBB transcription.
References provided by Crossref.org
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- $a Reading, N Scott $u 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.
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- $a 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 HBBS alleles inherited from her father; constituting her HBBS /HBBS -HBBA genotype. Further analyses revealed that proband's duplicated β-globin gene cluster (∼650 kb) encompassing HBBA 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 HBBA transcript was clearly detected by digital PCR. In this patient, the observed transcription from the duplicated, distally displaced HBBA 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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- $a Shooter, Claire $u Molecular Haematology, Division of Cancer Studies, King's College London Faculty of Life Sciences & Medicine, London, UK.
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- $a Song, Jihyun $u Division of Hematology, Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, Utah.
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- $a Lanikova, Lucie $u 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.
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- $a Clark, Barnaby $u 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.
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- $a Thein, Swee Lay $u 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.
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- $a Divoky, Vladimir $u 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.
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- $a Prchal, Josef T $u 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.
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