title: A new Krüppel-like factor 1 mutation (c.947G > A or p.C316Y) in humans causes β-thalassemia minor.
abstract: Here we describe a Japanese patient with mild β-thalassemia (β-thal) with an intact β-globin gene but a new missense mutation of c.947G > A or p.C316Y in the erythroid Krüppel-Like Factor (KLF1) gene which is strongly associated with the expression of the β-globin gene. The association of the KLF1 mutation with β-thal, is here described. The p.C316Y mutation occurred at one of the cysteines that constitute the second zinc finger motif of KLF1, and would have changed the zinc finger conformation to impair the DNA binding properties or the promoter function of the β-globin gene. Our expression study found that the mutant KLF1 gene had a markedly negative effect on the β-globin gene expression, or 7.0% of that of its normal counterpart. A presumed heterozygous state, or equimolar presence of the mutant and normal KLF1s reduced the expression rate to 70.0% of the normal alone. This degree of the decrease may explain the very mild phenotype of the patient's β-thal. Furthermore, the patient's whole-exome analysis using next-generation sequencing revealed that the β-thal defect is caused by only this KLF1 gene mutation. The Hb A2 and Hb F levels that are frequently elevated in KLF1 mutations were elevated by 4.1 and 1.3%, respectively, in this case. The contribution to their elevation by KLF1: p.C316Y is uncertain.
authors.affiliation: Department of Health Science, Yamaguchi University Graduate School of Medicine , Ube , Japan .
authors.forename: Takenori
authors.initials: T
authors.lastname: Nitta
authors.forename: Fumio
authors.initials: F
authors.lastname: Kawano
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamashiro
authors.forename: Fumiya
authors.initials: F
authors.lastname: Takagi
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Murata
authors.forename: Tatehiko
authors.initials: T
authors.lastname: Tanaka
authors.forename: Mella
authors.initials: M
authors.lastname: Ferania
authors.forename: Chris
authors.initials: C
authors.lastname: Adhiyanto
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hattori
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D003062:Codon; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D059472:Exome; D015870:Gene Expression; D023061:Gene Order; D017930:Genes, Reporter; D056426:Genetic Loci; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007564:Japan; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000235:genetics*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016335:Zinc Fingers / Q000235:genetics; D017086:beta-Thalassemia / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D003062:Codon; D018076:DNA, Complementary; D051741:Kruppel-Like Transcription Factors; C080774:erythroid Kruppel-like factor
keywords: Krüppel-Like Factor 1 (KLF1); next-generation sequencing; β-Globin expression; β-thalassemia (β-thal)