Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin.
| Title | Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. |
| Publication Type | Journal Article |
| Year of Publication | 2010 |
| Authors | Borg, J., Papadopoulos P., Georgitsi M., Gutiérrez L., Grech G., Fanis P., Phylactides M., Verkerk A. J. M. H., van der Spek P. J., Scerri C. A., Cassar W., Galdies R., van Ijcken W., Ozgür Z., Gillemans N., Hou J., Bugeja M., Grosveld F. G., von Lindern M., Felice A. E., Patrinos G. P., & Philipsen S. |
| Journal | Nat Genet |
| Volume | 42 |
| Issue | 9 |
| Pagination | 801-5 |
| Date Published | 2010 Sep |
| ISSN | 1546-1718 |
| Keywords | Adult, Cells, Cultured, Erythropoiesis, Family, Female, Fetal Hemoglobin, Gene Expression Regulation, Developmental, Genetic Diseases, Inborn, Humans, Kruppel-Like Transcription Factors, Loss of Heterozygosity, Male, Pedigree, Transcription Factors, Transfection |
| 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. |
| DOI | 10.1038/ng.630 |
| Alternate Journal | Nat. Genet. |
| PubMed ID | 20676099 |
| PubMed Central ID | PMC2930131 |
| Grant List | R01 HL073455 / HL / NHLBI NIH HHS / United States R01 HL073455-01 / HL / NHLBI NIH HHS / United States R01-HL073455 / HL / NHLBI NIH HHS / United States |
