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

J Borg, Petros Papadopoulos, Marianthi Georgitsi, Laura Gutierrez Gutierrez, G (Godfrey) Grech, Pavlos Fanis, M Phylactides, AJMH Verkerk, Peter van der Spek, CA Scerri, W Cassar, R Galdies, Wilfred van Ijcken, Zeliha Ozgur, Nynke Gillemans, Jun Hou, M Bugeja, Frank Grosveld, Marieke Lindern, AE FeliceGP Patrinos, Sjaak Philipsen

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298 Citations (Scopus)

Abstract

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 identified(1) 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 regulator(2). 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 expression(3). These observations provide a rationale for the effects of KLF1 haploinsufficiency on HbF levels.
Original languageUndefined/Unknown
Pages (from-to)801-U100
JournalNature Genetics
Volume42
Issue number9
Publication statusPublished - 2010

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