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.

• β-Globin expression
• β-thalassemia (β-thal)
• Krüppel-Like Factor 1 (KLF1)
• next-generation sequencing

Acknowledgements

Authors F.K., Y.Y. andY.H. collected the samples and clinical data; T.N., F.T., T.M. and T.T. performed research and analyzed data; T.N., F.T., M.F. and C.A. performed molecular diagnosis of thalassemia; T.N., Y.Y. and Y.H. designed the study, analyzed and interpreted the data and wrote the article.

Declaration of interest

This study was supported by JSPS KAKENHI Grant Number 25460686. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.