Novel variants of the KLF1 gene associated with the In(Lu) phenotype lead to alterations in protein structure

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BACKGROUND: phenotype and primarily caused by heterozygous variants in the erythroid-specific Krüeppel-like factor 1 (KLF1) gene. OBJECTIVES: This study aimed to analyse the genetic background of the In(Lu) phenotype in the Chinese population. METHODS: antigens using the gel card method. Targeted next-generation sequencing (NGS) was performed to identify potential variants in blood group genes and two transcription factors, KLF1 and GATA1, which were confirmed using Sanger and clonal sequencing. Homology modelling for both wild-type and mutant residues was performed using the Robetta platform, whereas changes in protein stability resulting from variants were assessed using the DynaMut web server. The functional impact of these variants was evaluated using the PolyPhen-2 and PROVEAN software tools. RESULTS: Four samples were identified as In(Lu). Two KLF1 variants had been previously reported, while two were novel: c.1004G>A (p.G335E) and c.1067 T>G (p.L356W). Three-dimensional molecular models indicated that both the p.E335 and p.W356 substitutions altered the distance to nearby amino acid sites. The p.W356 substitution also reduced ionic interactions between p.W356 and p.D352. Both variants were predicted to adversely affect protein function. CONCLUSION: Two novel KLF1 variants, c.1004G>A (p.G335E) and c.1067 T>G (p.L356W), were detected in two Chinese donors, suggesting an association with the In(Lu) phenotype.

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