Erythroid Krüppel-like factor mutations are relatively more common in a thalassemia endemic region and ameliorate the clinical and hematological severity of β-thalassemia

Mutations in human Krüppel-like factor 1 (KLF1) have recently been reported to be responsible for increased fetal hemoglobin (HbF) and hemoglobin A2 (HbA2). As increased HbF and HbA2 levels are important features of β-thalassemia, we examined whether there is any relationship between KLF1 mutation and β-thalassemia in China. For this, we first studied the incidence of KLF1 mutations in two Chinese populations: 3839 individuals from a thalassemia endemic region in south China and 1190 individuals from a non-thalassemia endemic region in north China. Interestingly we found that the prevalence of KLF1 mutations is significantly higher in thalassemia endemic region than that in non-thalassemia endemic region (1.25% versus 0.08%). Furthermore, we identified seven functional variants including four previously reported (p.Gly176AlafsX179, p.Ala298Pro, p.Thr334Arg and c.913+1G>A) and three novel ones (p.His299Asp, p.Cys341Tyr and p.Glu5Lys) in southern China. The two most common mutations, p.Gly176AlafsX179 and p.His299Asp, accounted for 90.6% of the total. We found that zinc-finger mutations in KLF1 were selectively represented in 12 β-thalassemia intermedia patients, and resulted in significantly different transfusion-free survival curves. Our findings suggest that KLF1 mutations occur selectively in the presence of β-thalassemia to increase the production of HbF which in turn ameliorates the clinical severity of β-thalassemia. For personal use only. on September 14, 2017. by guest www.bloodjournal.org From