ArticlePLoS genetics2021
Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing.
Article in PLoS genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 22 citations in OpenAlex.
- Article
- Zinc finger proteins (ZFPs) in health and disease.Molecular biomedicine · 2026Review
- Article
- Review
- Multimeric transcription factor BCL11A utilizes two zinc-finger tandem arrays to bind clustered short sequence motifs.Nature communications · 2025Article
- Solution structure of the Z0 domain from transcription repressor BCL11A sheds light on the sequence properties of protein-binding zinc fingers.Protein science : a publication of the Protein Society · 2025Article
- BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations.European journal of human genetics : EJHG · 2025Article
- Structural insights into the DNA-binding mechanism of BCL11A: The integral role of ZnF6.Structure (London, England : 1993) · 2024Article
- A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing.Science (New York, N.Y.) · 2024Article
- Transcriptional regulators of fetal hemoglobin.Hematology, transfusion and cell therapy · 2024Review
- C2H2 Zinc Finger Transcription Factors Associated with Hemoglobinopathies.Journal of molecular biology · 2024Review
- Base editing of key residues in the BCL11A-XL-specific zinc finger domains derepresses fetal globin expression.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Transcriptional Repressor BCL11A in Erythroid Cells.Advances in experimental medicine and biology · 2024Review
- NMR structure verifies the eponymous zinc finger domain of transcription factor ZNF750.Journal of structural biology: X · 2023Article
- CRISPR-Cas9 base editors and their current role in human therapeutics.Cytotherapy · 2023Review
- Single Nucleotide Polymorphisms inDiagnostics (Basel, Switzerland) · 2022Review
- Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and β-thalassemia. BCL11A has been identified as a key regulator of HbF silencing, although its precise mechanisms of action remain incompletely understood. Recent studies have identified pathogenic mutations that cause heterozygous loss-of-function of BCL11A and result in a distinct neurodevelopmental disorder that is characterized by persistent HbF expression. While the majority of cases have deletions or null mutations causing haploinsufficiency of BCL11A, several missense variants have also been identified. Here, we perform functional studies on these variants to uncover specific liabilities for BCL11A's function in HbF silencing. We find several mutations in an N-terminal C2HC zinc finger that increase proteasomal degradation of BCL11A. We also identify a distinct C-terminal missense variant in the fifth zinc finger domain that we demonstrate causes loss-of-function through disruption of DNA binding. Our analysis of missense variants causing loss-of-function in vivo illuminates mechanisms by which BCL11A silences HbF and also suggests potential therapeutic avenues for HbF induction to treat sickle cell disease and β-thalassemia.
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Registered trials
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