TY - JOUR
T1 - Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin
AU - Borg, Joseph
AU - Papadopoulos, Petros
AU - Georgitsi, Marianthi
AU - Gutiérrez, Laura
AU - Grech, Godfrey
AU - Fanis, Pavlos
AU - Phylactides, Marios
AU - Verkerk, Annemieke J. M. H.
AU - van der Spek, Peter J.
AU - Scerri, Christian A.
AU - Cassar, Wilhelmina
AU - Galdies, Ruth
AU - van Ijcken, Wilfred
AU - Ozgür, Zeliha
AU - Gillemans, Nynke
AU - Hou, Jun
AU - Bugeja, Marisa
AU - Grosveld, Frank G.
AU - von Lindern, Marieke
AU - Felice, Alex E.
AU - Patrinos, George P.
AU - Philipsen, Sjaak
PY - 2010
Y1 - 2010
N2 - 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 regulator. 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. These observations provide a rationale for the effects of KLF1 haploinsufficiency on HbF levels
AB - 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 regulator. 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. These observations provide a rationale for the effects of KLF1 haploinsufficiency on HbF levels
U2 - https://doi.org/10.1038/ng.630
DO - https://doi.org/10.1038/ng.630
M3 - Article
C2 - 20676099
SN - 1061-4036
VL - 42
SP - 801
EP - 805
JO - Nature Genetics
JF - Nature Genetics
IS - 9
ER -