BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations
Open accessAbstract
A transition from fetal hemoglobin (HbF) to adult hemoglobin (HbA) normally occurs within a few months after birth. Increased production of HbF after this period of infancy ameliorates clinical symptoms of the major disorders of adult β-hemoglobin: β-thalassemia and sickle cell disease. The transcription factor BCL11A silences HbF and has been an attractive therapeutic target for increasing HbF levels; however, it is not clear to what extent BCL11A inhibits HbF production or mediates other developmental functions in humans. Here, we identified and characterized 3 patients with rare microdeletions of 2p15-p16.1 who presented with an autism spectrum disorder and developmental delay. Moreover, these patients all exhibited substantial persistence of HbF but otherwise retained apparently normal hematologic and immunologic function. Of the genes within 2p15-p16.1, only BCL11A was commonly deleted in all of the patients. Evaluation of gene expression data sets from developing and adult human brains revealed that BCL11A expression patterns are similar to other genes associated with neurodevelopmental disorders. Additionally, common SNPs within the second intron of BCL11A are strongly associated with schizophrenia. Together, the study of these rare patients and orthogonal genetic data demonstrates that BCL11A plays a central role in silencing HbF in humans and implicates BCL11A as an important factor for neurodevelopment.
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Follow-up of GWAS for fetal hemoglobin revealed BCL11A to be a key regulator of fetal hemoglobin silencing.
“The follow up of these GWAS for HbF revealed BCL11A to be a key regulator of HbF silencing (Basak et al., 2015; Sankaran et al., 2008, 2009), a finding that has now led to further biological and therapeutic insights (Liu et al., 2018).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Basak et al., 2015
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- Authors
- Basak, A., Hancarova, M., Ulirsch, J. C., Balci, T. B., Trkova, M., Pelisek, M., Vlckova, M., Muzikova, K., Cermak, J., Trka, J., Dyment, D. A., Orkin, S. H., Daly, M. J., Sedlacek, Z., & Sankaran, V. G.
- Affiliations
- Broad Institute (US)
- Strakonice Hospital (CZ)
- Charles University (CZ)
- University of Ottawa (CA)
- Boston Children's Hospital (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2015-05-04
- Volume
- 125
- Issue
- 6
- Pages
- 2363-2368
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4497765
- OpenAlex
- W2127724005
- Cited by
- 147
- References
- 24
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 12 · 2023: 15 · 2022: 6 · 2021: 16 · 2020: 14 · 2019: 15 · 2018: 17 · 2017: 16 · 2016: 18 · 2015: 5
- FWCI
- 10.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Scholarship@Western (Western University) (submittedVersion)
- Funders
- Univerzita Karlova v Praze (00064203)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL032259, U01HL117720, R21HL120791)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103794)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- BCL11A, autism spectrum disorder, developmental delay, brain development, schizophrenia susceptibility, intronic SNPs, beta-thalassemia, sickle cell disease, brain gene expression
- MeSH terms
- Adult, Base Sequence, Carrier Proteins, Child, Child Development Disorders, Pervasive, Child, Preschool, Fetal Hemoglobin, Gene Expression Regulation, Humans, Infant, Introns, Male, Nuclear Proteins, Repressor Proteins, Schizophrenia, Sequence Deletion, Polymorphism, Single Nucleotide
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