EKLF Gene Expression in β-thalassemia

Rofaida Hassan Ahmed

Status: Not yet enrolling

Conditions: β-thalassemia

Treatments: Diagnostic Test: PCR

Study type: Observational

Funder types: Other

Identifiers

NCT06440603

β-thalassemia

Details and patient eligibility

About

1. Studying the effect of expression pattern of EKLF gene in β-thalassemic patients.
2. Detecting the correlation between the gene expression of EKLF and the clinical phenotype of β-thalassemic patients.

Full description

β-thalassemia is a common inherited disorder caused by absent or reduced synthesis of the hemoglobin subunit beta (beta globin chain) , it has 3 clinical types; minor which is a carrier state, intermedia and major which are differentiated by blood transfusion dependency and lab findings.

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.

Enrollment: 150 estimated patients

Sex: All

Ages: 5 to 80 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• patients with β-thalassemia (major and intermedia).
• patients are of both sexes (male or female) at any age

Exclusion criteria

• patients with any other types of hemolytic anaemia

Trial design

150 participants in 3 patient groups

Group I

Description:

Age and sex matched healthy Control

Treatment:

Diagnostic Test: PCR

Group 2

Description:

50 patients with β-thalassemia major

Treatment:

Diagnostic Test: PCR

Group 3

Description:

50 patients with β-thalassemia intermedia

Treatment:

Diagnostic Test: PCR