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Title: Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin
Authors: Borg, Joseph
Papadopoulos, Petros
Georgitsi, Marianthi
Gutierrez, Laura
Grech, Godfrey
Fanis, Pavlos
Phylactides, Marios
Verkerk, Annemieke J.M.H.
van der Spek, Peter J.
Scerri, Christian A.
Cassar, Wilhelmina
Galdies, Ruth
van IJcken, Wilfred
Ozgur, Zeliha
Gillemans, Nynke
Hou, Jun
Bugeja, Marisa
Grosveld, Frank G.
von Lindern, Marieke
Felice, Alex E.
Patrinos, George P.
Philipsen, Sjaak
Keywords: Genetics -- Malta -- Case studies
Hemoglobins, Abnormal -- Genetics
Issue Date: 2010
Citation: Borg, J., Papadopoulos, P.,Georgitsi, M.,Guitierrez, L., Grech, G., Fanis, P.,...Philipsen, S. (2010). Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nature Genetics, 42(9), 801-807.
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 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.
Appears in Collections:Melitensia Works - ERCSciNHB

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