KLF1 mutations are relatively more common in a thalassemia endemic region and ameliorate the 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). Because 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. To do this, we first studied the incidence of KLF1 mutations in 2 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 the thalassemia endemic region than that in non-thalassemia endemic region (1.25% vs 0.08%). Furthermore, we identified 7 functional variants including 4 previously reported (p.Gly176AlafsX179, p.Ala298Pro, p.Thr334Arg, and c.913+1G>A) and 3 novel variants (p.His299Asp, p.Cys341Tyr, and p.Glu5Lys) in southern China. The 2 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.
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China;
Dun
D
Liu
Department of Hematology, 303rd Hospital of the People's Liberation Army, Nanning, Guangxi, China;
Xinhua
X
Zhang
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China;
Lihua
L
Yu
Department of Birth Health and Heredity, Liuzhou Women and Children Care Hospital, Liuzhou, Guangxi, China;
Ren
R
Cai
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China;
Xiaoxia
X
Ma
Prenatal Diagnostic Center, Guangxi Zhuang Autonomous Region Women and Children Care Hospital, Nanning, Guangxi, China;
Chengguang
C
Zheng
Department of Birth Health and Heredity, Zhuhai Women and Children Care Hospital, Zhuhai, Guangdong, China;
Yuqiu
Y
Zhou
Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Medicine, Shandong University, Jinan, Shandong, China; and.
Qiji
Q
Liu
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China;
Xiaofeng
X
Wei
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China;
Li
L
Lin
Department of Birth Health and Heredity, Liuzhou Women and Children Care Hospital, Liuzhou, Guangxi, China;
Tizhen
T
Yan
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China;
Jiwei
J
Huang
Red Cell Physiology Laboratory, New York Blood Center, New York, NY.
Narla
N
Mohandas
Red Cell Physiology Laboratory, New York Blood Center, New York, NY.
Xiuli
X
An
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China;
Xiangmin
X
Xu
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002681:China / Q000453:epidemiology; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D009154:Mutation; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016335:Zinc Fingers / Q000235:genetics; D017086:beta-Thalassemia / Q000097:blood / Q000453:epidemiology* / Q000235:genetics*
D051741:Kruppel-Like Transcription Factors; C080774:erythroid Kruppel-like factor; D005319:Fetal Hemoglobin