Genetic variation of Krüppel-like factor 1 (KLF1) and fetal hemoglobin (HbF) levels in β0-thalassemia/HbE disease
Heterogeneity of HbF levels in β0-thalassemia/HbE disease has been reported to be associated with variations in clinical manifestations of the disease, and several genetic-modifying factors beyond the β-globin gene cluster have been identified as HbF regulators. Down-regulation or heterozygous mutations of Krüppel-like factor 1 (KLF1) is associated with elevated HbF levels in non-thalassemia subjects. This study confirms that experimental down-regulation of KLF1 in β0-thalassemia/HbE-derived erythroblasts significantly increases HbF production (up to 52.3 ± 2.4%), albeit with slightly delayed erythroid terminal differentiation. KLF1 exome sequencing of 130 Thai β0-thalassemia/HbE patients without co-inheritance of α-thalassemia found six patients with KLF1 heterozygous mutations including rs2072596 (p.F182L; n = 5) and rs745347362 (p.P284L; n = 1) missense mutations. However, while these patients had high HbF levels (38.1 ± 7.5%), they were all associated with a severe clinical phenotype. These results suggest that while reduction of KLF1 expression in β0-thalassemia/HbE erythroblasts can increase HbF levels, it is not sufficient to alleviate the clinical phenotype.
KeywordsKrüppel-like factor 1 KLF1 β-Thalassemia Hemoglobin E Hemoglobin F
This work was supported by grants from Mahidol University and by a National Science and Technology Development Agency (NSTDA) Research Chair Grant. PK is supported by a Thailand Graduate Institute of Science and Technology (TGIST) scholarship (TG-22-14-58-037D) from the National Science and Technology Development Agency (NSTDA), Thailand. We sincerely thank all donors who participated in this study.
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Conflict of interest
The authors have no conflict of interest.
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