title: Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin.
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 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.
authors.affiliation: Laboratory of Molecular Genetics, Department of Physiology and Biochemistry, University of Malta, Msida, Malta.
authors.forename: Joseph
authors.initials: J
authors.lastname: Borg
authors.forename: Petros
authors.initials: P
authors.lastname: Papadopoulos
authors.forename: Marianthi
authors.initials: M
authors.lastname: Georgitsi
authors.forename: Laura
authors.initials: L
authors.lastname: Gutiérrez
authors.forename: Godfrey
authors.initials: G
authors.lastname: Grech
authors.forename: Pavlos
authors.initials: P
authors.lastname: Fanis
authors.forename: Marios
authors.initials: M
authors.lastname: Phylactides
authors.forename: Annemieke J M H
authors.initials: AJ
authors.lastname: Verkerk
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van der Spek
authors.forename: Christian A
authors.initials: CA
authors.lastname: Scerri
authors.forename: Wilhelmina
authors.initials: W
authors.lastname: Cassar
authors.forename: Ruth
authors.initials: R
authors.lastname: Galdies
authors.forename: Wilfred
authors.initials: W
authors.lastname: van Ijcken
authors.forename: Zeliha
authors.initials: Z
authors.lastname: Ozgür
authors.forename: Nynke
authors.initials: N
authors.lastname: Gillemans
authors.forename: Jun
authors.initials: J
authors.lastname: Hou
authors.forename: Marisa
authors.initials: M
authors.lastname: Bugeja
authors.forename: Frank G
authors.initials: FG
authors.lastname: Grosveld
authors.forename: Marieke
authors.initials: M
authors.lastname: von Lindern
authors.forename: Alex E
authors.initials: AE
authors.lastname: Felice
authors.forename: George P
authors.initials: GP
authors.lastname: Patrinos
authors.forename: Sjaak
authors.initials: S
authors.lastname: Philipsen
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D004920:Erythropoiesis / Q000235:genetics; D005190:Family; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D019656:Loss of Heterozygosity / Q000502:physiology; D008297:Male; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection
chemical_list: D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; C080774:erythroid Kruppel-like factor; D005319:Fetal Hemoglobin