Genetic variation of Krüppel-like factor 1 (KLF1) and fetal hemoglobin (HbF) levels in β0-thalassemia/HbE disease

被引：0
作者：
Pinyaphat Khamphikham
Orapan Sripichai
Thongperm Munkongdee
Suthat Fucharoen
Sissades Tongsima
Duncan R. Smith
机构：
[1] Mahidol University,Institute of Molecular Biosciences
[2] National Center for Genetic Engineering and Biotechnology,undefined
[3] National Science and Technology Development Agency,undefined
来源：
International Journal of Hematology | 2018年 / 107卷
关键词：
Krüppel-like factor 1; KLF1; β-Thalassemia; Hemoglobin E; Hemoglobin F;
D O I：
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中图分类号：
学科分类号：
摘要：
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.
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页码：297 / 310
页数：13
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