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Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin


Hereditary persistence of fetal hemoglobin (HPFH) is characterized by persistent high levels of fetal hemoglobin (HbF) in adults. Several contributory factors, both genetic and environmental, have been identified1 but others remain elusive. HPFH was found in 10 of 27 members from a Maltese family. We used a genome-wide SNP scan followed by linkage analysis to identify a candidate region on chromosome 19p13.12–13. Sequencing revealed a nonsense mutation in the KLF1 gene, p.K288X, which ablated the DNA-binding domain of this key erythroid transcriptional regulator2. Only family members with HPFH were heterozygous carriers of this mutation. Expression profiling on primary erythroid progenitors showed that KLF1 target genes were downregulated in samples from individuals with HPFH. Functional assays suggested that, in addition to its established role in regulating adult globin expression, KLF1 is a key activator of the BCL11A gene, which encodes a suppressor of HbF expression3. These observations provide a rationale for the effects of KLF1 haploinsufficiency on HbF levels.

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Figure 1: Chromosome 19 locus linked to HPFH in a Maltese family.
Figure 2: KLF1 target genes are downregulated in KLF1 p.K288X heterozygous HEPs.
Figure 3: Increased HBG1/HBG2 expression after knockdown of KLF1 in normal HEPs.
Figure 4: Expression of exogenous KLF1 in HEPs from donors with HPFH.
Figure 5: KLF1 binds to the promoter of the BCL11A gene in vivo.

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We thank the family members for their cooperation; T. van Gent for help with statistical analysis; T. van Dijk for expertise in lentiviral technology; N. Papazian for preparation of human fetal liver samples; and M. Pizzuto for administrative support. The population samples from Malta were obtained from the Malta BioBank (EuroBioBank). Recombinant human erythropoietin (Epo) was a kind gift from Ortho-Biotech, and recombinant human Stem Cell Factor (SCF) was a kind gift from Amgen. Supported by the University of Malta and Mater Dei Hospital (A.E.F.); the Malta Government (J.B.); the European Molecular Biology Organization (J.B., P.P.); the Netherlands Scientific Organization (VENI 863.09.012 to L.G. and DN 82-294 and 912-07-019 to S.P.); the Netherlands Genomics Initiative, Erasmus MC (MRace; 296088 to S.P.); the Landsteiner Foundation for Blood Transfusion Research (0615 to S.P.); the Centre for Biomedical Genetics (F.G.G.); the European Commission FP6 EuTRACC consortium (037445 to F.G.G.); the US National Institutes of Health (NIH) (R01-HL073455 to F.G.G.); the Research Promotion Foundation of Cyprus (ΠΔE046_02 to G.P.P.); and the European Commission FP7 GEN2PHEN (200754 to G.P.P).

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F.G.G., A.E.F., G.P.P. and S.P. designed experiments. J.B., P.P., M.G., L.G., G.G., P.F., M.P., C.A.S., W.C., R.G., Z.Ö., N.G. and M.v.L. performed experiments. J.B., P.P., M.G., L.G. and G.G. analyzed results. P.J.v.d.S., F.G.G., A.E.F., G.P.P. and S.P. supervised data analysis. P.J.v.d.S., W.v.IJ. and M.B. provided expertise, analysis tools and infrastructure. A.J.M.H.V., J.H. and M.B. analyzed data. J.B., P.P., M.G., F.G.G., M.v.L., A.E.F., G.P.P. and S.P. wrote the paper.

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Correspondence to Alex E Felice, George P Patrinos or Sjaak Philipsen.

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Borg, J., Papadopoulos, P., Georgitsi, M. et al. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet 42, 801–805 (2010).

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