Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin
| Autor: | Sjaak Philipsen, Petros Papadopoulos, Annemieke J.M.H. Verkerk, Godfrey Grech, Marianthi Georgitsi, Alex E. Felice, Frank Grosveld, Ruth Galdies, Wilhelmina Cassar, Nynke Gillemans, Pavlos Fanis, Marieke von Lindern, Jun Hou, Peter J. van der Spek, Joseph Borg, Marisa Bugeja, Christian Scerri, Laura Gutierrez, Zeliha Ozgur, Marios Phylactides, George P. Patrinos, Wilfred F. J. van IJcken |
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| Přispěvatelé: | Landsteiner Laboratory, Cell biology, Hematology, Pathology |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Regulation of gene expression
Genetics 0303 health sciences Hereditary persistence of fetal hemoglobin Nonsense mutation Hemoglobins Abnormal -- Genetics GATA1 KLF1 Biology medicine.disease Molecular biology Article Genetics -- Malta -- Case studies 03 medical and health sciences 0302 clinical medicine 030220 oncology & carcinogenesis hemic and lymphatic diseases Fetal hemoglobin medicine Globin Haploinsufficiency 030304 developmental biology |
| Zdroj: | EUR Research Portal Nature genetics, 42(9), 801-805. Nature Publishing Group Nature genetics Nature Genetics, 42(9), 801-U100. Nature Publishing Group Nature Genetics; Vol 42 |
| ISSN: | 1061-4036 |
| Popis: | 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. peer-reviewed |
| Databáze: | OpenAIRE |
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