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 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.
Borg
Joseph
J
Laboratory of Molecular Genetics, Department of Physiology and Biochemistry, University of Malta, Msida, Malta.
Papadopoulos
Petros
P
Georgitsi
Marianthi
M
Gutiérrez
Laura
L
Grech
Godfrey
G
Fanis
Pavlos
P
Phylactides
Marios
M
Verkerk
Annemieke J M H
AJ
van der Spek
Peter J
PJ
Scerri
Christian A
CA
Cassar
Wilhelmina
W
Galdies
Ruth
R
van Ijcken
Wilfred
W
Ozgür
Zeliha
Z
Gillemans
Nynke
N
Hou
Jun
J
Bugeja
Marisa
M
Grosveld
Frank G
FG
von Lindern
Marieke
M
Felice
Alex E
AE
Patrinos
George P
GP
Philipsen
Sjaak
S
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
D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; C080774:erythroid Kruppel-like factor; D005319:Fetal Hemoglobin