Study Results
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Basic Information
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NOT_YET_RECRUITING
150 participants
OBSERVATIONAL
2024-07-01
2027-07-01
Brief Summary
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2. Detecting the correlation between the gene expression of EKLF and the clinical phenotype of β-thalassemic patients.
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Detailed Description
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In β-thalassemia, insufficient production of the β-globin molecule results in an excess of free α-globin chains that can precipitate within erythroid precursors, impairing their maturation and leads to death of these precursors and ineffective production of erythroid cells. As a result, a significant anaemia occurs and the consequent expansion of erythroid precursors can lead to secondary problems in bones and other organs.
These mutations are primarily point mutations that affect transcriptional control, translation, and splicing of the beta haemoglobin gene and gene expression.
The frequency of beta-thalassemia mutations varies by regions of the world with the highest prevalence in the Mediterranean, the Middle East, and Southeast and Central Asia. Approximately 68000 children are born with beta-thalassemia. Its prevalence is 80-90 million carriers, around 1.5% of the global population.
Erythroid Krüppel-like factor (EKLF or KLF1) is a transcriptional regulator that plays a major role in lineage-restricted control of gene expression. KLF1 expression and activity are tightly controlled in a temporal and differentiation stage-specific manner. The mechanisms by which KLF1 is regulated encompass a range of biological processes, including control of KLF1 RNA transcription, protein stability, localization, and posttranslational modifications. Intact KLF1 regulation is essential to correctly regulate erythroid function by gene transcription and to maintain hematopoietic lineage homeostasis by ensuring a proper balance of erythroid/megakaryocytic differentiation. In turn, KLF1 regulates erythroid biology by a wide variety of mechanisms, including gene activation and repression by regulation of chromatin configuration, transcriptional initiation and elongation, and localization of gene loci to transcription factories in the nucleus.
Previous studies have shown that EKLF plays a critical role in regulating the developmental switch between fetal and adult haemoglobin expression, both by direct activation of β-globin and indirect repression of γ-globin gene expression in adult erythroid progenitors via regulation of Bcl11a and ZBTB7a and PUM1.
PUM1 is a direct posttranscriptional regulator of β-globin switching, whose expression is regulated by the erythroid master transcription factor erythroid Krüppel-like factor (EKLF/KLF1), peaks during erythroid differentiation, binds γ-globin messenger RNA (mRNA), and reduces γ-globin (HBG1) mRNA stability and translational efficiency, which culminates in reduced γ-globin protein levels.
So, EKLF is too important in erythropoiesis and Hb switching that there are clinical trials nowadays depending on the molecules that targeted by EKLF (eg:Bcl11a, ZBTB7a and PUM1) and their role in Hb switching in treatment of thalassemia and other haemolytic anaemias as sickle cell anaemia.
Conditions
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Study Design
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CASE_CONTROL
RETROSPECTIVE
Study Groups
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Group I
Age and sex matched healthy Control
PCR
Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for detection of EKLF:
* The method of total RNA extraction: TRIZOL and TRIZOL LS.
* The purity and concentration of the RNA will be measured using Nano Drop 2000 instument.
* cDNA will be done with primers using thr Goscript Reverse Transcription System
Group 2
50 patients with β-thalassemia major
PCR
Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for detection of EKLF:
* The method of total RNA extraction: TRIZOL and TRIZOL LS.
* The purity and concentration of the RNA will be measured using Nano Drop 2000 instument.
* cDNA will be done with primers using thr Goscript Reverse Transcription System
Group 3
50 patients with β-thalassemia intermedia
PCR
Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for detection of EKLF:
* The method of total RNA extraction: TRIZOL and TRIZOL LS.
* The purity and concentration of the RNA will be measured using Nano Drop 2000 instument.
* cDNA will be done with primers using thr Goscript Reverse Transcription System
Interventions
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PCR
Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for detection of EKLF:
* The method of total RNA extraction: TRIZOL and TRIZOL LS.
* The purity and concentration of the RNA will be measured using Nano Drop 2000 instument.
* cDNA will be done with primers using thr Goscript Reverse Transcription System
Eligibility Criteria
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Inclusion Criteria
* patients are of both sexes (male or female) at any age
Exclusion Criteria
5 Years
80 Years
ALL
Yes
Sponsors
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Rofaida Hassan Ahmed
OTHER
Responsible Party
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Rofaida Hassan Ahmed
Principle investigator
Principal Investigators
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Eman Naser Eldin
Role: STUDY_DIRECTOR
Assiut University
Sherif Helmy
Role: STUDY_DIRECTOR
Assiut University
Reem Elagoz
Role: STUDY_DIRECTOR
Assiut University
Central Contacts
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References
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Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med. 2013 Jan 1;3(1):a011643. doi: 10.1101/cshperspect.a011643.
Cao A, Galanello R. Beta-thalassemia. Genet Med. 2010 Feb;12(2):61-76. doi: 10.1097/GIM.0b013e3181cd68ed.
Origa R. beta-Thalassemia. Genet Med. 2017 Jun;19(6):609-619. doi: 10.1038/gim.2016.173. Epub 2016 Nov 3.
Yien YY, Bieker JJ. EKLF/KLF1, a tissue-restricted integrator of transcriptional control, chromatin remodeling, and lineage determination. Mol Cell Biol. 2013 Jan;33(1):4-13. doi: 10.1128/MCB.01058-12. Epub 2012 Oct 22.
Borg J, Papadopoulos P, Georgitsi M, Gutierrez L, Grech G, Fanis P, Phylactides M, Verkerk AJ, van der Spek PJ, Scerri CA, Cassar W, Galdies R, van Ijcken W, Ozgur Z, Gillemans N, Hou J, Bugeja M, Grosveld FG, von Lindern M, Felice AE, Patrinos GP, Philipsen S. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet. 2010 Sep;42(9):801-5. doi: 10.1038/ng.630. Epub 2010 Aug 1.
Elagooz R, Dhara AR, Gott RM, Adams SE, White RA, Ghosh A, Ganguly S, Man Y, Owusu-Ansah A, Mian OY, Gurkan UA, Komar AA, Ramamoorthy M, Gnanapragasam MN. PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin. Blood Adv. 2022 Dec 13;6(23):6016-6022. doi: 10.1182/bloodadvances.2021006730.
Siatecka M, Soni S, Planutis A, Bieker JJ. Transcriptional activity of erythroid Kruppel-like factor (EKLF/KLF1) modulated by PIAS3 (protein inhibitor of activated STAT3). J Biol Chem. 2015 Apr 10;290(15):9929-40. doi: 10.1074/jbc.M114.610246. Epub 2015 Feb 24.
Other Identifiers
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β-thalassemia
Identifier Type: -
Identifier Source: org_study_id
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