Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin
Open accessAbstract
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.
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- 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., Özgür, Z., Gillemans, N., Hou, J., Bugeja, M., Grosveld, F. G., von Lindern, M., Felice, A. E., Patrinos, G. P., & Philipsen, S.
- Affiliations
- University of Malta (MT)
- Erasmus MC (NL)
- University of Patras (GR)
- Cyprus Institute of Neurology and Genetics (CY)
- Corresponding author
- Felice, Alex E
- Patrinos, George P
- Philipsen, Sjaak
- ORCID
- Venue
- Nature Genetics
- Published
- 2010-08-01
- Volume
- 42
- Issue
- 9
- Pages
- 801-805
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2930131
- OpenAlex
- W2155119455
- Semantic Scholar
- a6949750c6a67fb6e5bd26168ea692c9712fbc74
- Cited by
- 371
- References
- 37
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 19 · 2023: 16 · 2022: 15 · 2021: 25 · 2020: 21 · 2019: 17 · 2018: 27 · 2017: 29 · 2016: 32 · 2015: 31 · 2014: 21 · 2013: 26 · 2012: 32
- FWCI
- 14.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- OAR@UM (University of Malta) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (863.09.012, 912-07-019)
- National Institutes of Health (5r01hl073455-02)
- National Heart, Lung, and Blood Institute (R01-HL073455)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- hereditary persistence of fetal hemoglobin, KLF1, haploinsufficiency, BCL11A, erythroid transcription factor, nonsense mutation, DNA-binding domain, erythroid progenitor cells, chromosome 19p13, globin gene expression
- MeSH terms
- Adult, Cells, Cultured, Erythropoiesis, Family, Female, Fetal Hemoglobin, Humans, Male, Pedigree, Transcription Factors, Transfection, Gene Expression Regulation, Developmental, Loss of Heterozygosity, Genetic Diseases, Inborn, Kruppel-Like Transcription Factors
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