A novel mutation in the erythroid transcription factor KLF1 is likely responsible for ameliorating β‐thalassemia major

Abstract

We describe the identification of a novel missense mutation in the second zinc finger of KLF1 in two siblings who, based on their genotype, are predicted to suffer from beta thalassemia major but are, in fact, transfusion‐free and in good health. These individuals, as well as two additional members of the same family also carrying this KLF1 mutation, exhibit high levels of fetal hemoglobin (HbF). KLF1 is an erythroid transcription factor, which plays a critical role in the regulation of the developmental switch between fetal and adult hemoglobin by regulating the expression of a multitude of genes including that of BCL11A. The mutation appears to be the main candidate responsible for the beta thalassemia‐ameliorating effect as this segregates with the observed phenotype and also exogenous expression of the KLF1 mutant protein in human erythroid progenitor cells resulted in the induction of γ‐globin, without, however, affecting BCL11A levels. This report adds to the weight of evidence that heterozygous KLF1 mutations can ameliorate the severity of the β‐thalassemia major phenotype.

Severe neonatal haemolytic anaemia caused by compound heterozygous KLF1 mutations: report of four families and literature review

“…KLF1 mutations can cause borderline high Hb A 2 levels 16–18 . KLF1 has also been reported to ameliorate the severity of beta‐thalassaemia disease 19–21 . The findings were demonstrated in a pair of twins who had beta‐thalassaemia major with discrepant clinical severity.…”

“…[16][17][18] KLF1 has also been reported to ameliorate the severity of beta-thalassaemia disease. [19][20][21] The findings were demonstrated in a pair of twins who had beta-thalassaemia major with discrepant clinical severity. The twin who harboured a co-inherited KLF1 mutation was non-transfusiondependent.…”

Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β–Thalassemia

“…KLF1 is a zinc-finger DNA binding protein that binds specifically to the 5′-CCMCRCCCN-3′ motif on most erythroid-specific genes. Furthermore, KLF1 acts as a positive regulator of BCL11A transcription factor expression to control the levels of HbF [ 39 ].…”

“…The latest findings by Fanis et al [ 39 ] revealed a novel missense mutation in the second zinc-finger domain of the KLF1 protein, in two siblings who were predicted to have β –thalassemia major based on their genotype (IVS1-110); however, they were both transfusion-free and healthy. Another two family members also exhibited a high level of HbF while carrying a similar KLF1 mutation.…”

Hyperhaemolysis in a pregnant woman with a homozygous β0‐thalassemia mutation and two genetic modifiers

“…Physical examination was unremarkable, without signs of anaemia, such as jaundice, paleness, splenomegaly and hepatomegaly. To investigate her unexpected mild phenotype, known genetic modifiers that ameliorate the severity of β‐thalassemia were analysed (Fanis et al, 2019 ; Lai et al, 2016 ; Razak et al, 2018 ). A heterozygous KLF1 mutation (c.519_525dup) and two homozygous SNP variants, rs7776054 and rs9399137, in the HBS1L ‐ MYB locus were identified [Figure 1d ].…”