title: Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin.
abstract: Krüppel-like factor 1 (KLF1) regulates erythroid lineage commitment, globin switching, and the terminal maturation of red blood cells. Variants in human KLF1 have been identified as an important causative factor in a wide spectrum of phenotypes. This study investigated two unrelated male children in China who had refractory anemia associated with poikilocythemia. These were accompanied by an upregulation of biochemical markers of hemolysis, along with abnormal hemoglobin (Hb) level and elevated reticulocyte counts. Next-generation sequencing revealed that the patients were compound heterozygotes for a KLF1 frameshift mutation c.525_526insCGGCGCC (p.(Gly176ArgfsTer179)) and one of two missense variants, c.892 G>C (p.(Ala298Pro)) and c.1012C>T (p.(Pro338Ser)). The subjects had microcytic hypochromic anemia, and their healthy parents had single mutation. The two missense mutations affected a highly conserved codon in the zinc finger DNA-binding domain of KLF1, but the protein stability was unaffected in K-562 cells. A KLF1-targeted promoter-reporter assay showed that the two mutations reduce the expression of the HBB, BCL11A, and CD44 genes involved in erythropoiesis, with consequent dyserythropoiesis and an α/non-α chain imbalance. A systematic analysis was performed of the phenotypes associated with the KLF1 mutations in the two families, and the clinical characteristics and differential diagnoses of the disease are presented. This is the first report of an autosomal recessive anemia presenting with microcytic hypochromia, abnormal Hb profile, and other distinctive erythrocyte phenotypes, and provides insight into the multiple roles of KLF1 during erythropoiesis.
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Hematology, 303rd Hospital of the People's Liberation Army, Nanning, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Dun
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Shang
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Fu
authors.initials: F
authors.lastname: Xiong
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Hematology, 303rd Hospital of the People's Liberation Army, Nanning, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Xu
mesh_terms: D000595:Amino Acid Sequence; D000747:Anemia, Hypochromic / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D002681:China; D003062:Codon / Q000235:genetics; D004920:Erythropoiesis / Q000235:genetics; D005319:Fetal Hemoglobin / Q000235:genetics*; D006402:Hematologic Diseases / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D020014:K562 Cells; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D003062:Codon; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; C080774:erythroid Kruppel-like factor; D005319:Fetal Hemoglobin