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Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing
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 mut...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530301/ https://www.ncbi.nlm.nih.gov/pubmed/34634037 http://dx.doi.org/10.1371/journal.pgen.1009835 |
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author | Shen, Yong Li, Rick Teichert, Kristian Montbleau, Kara E. Verboon, Jeffrey M. Voit, Richard A. Sankaran, Vijay G. |
author_facet | Shen, Yong Li, Rick Teichert, Kristian Montbleau, Kara E. Verboon, Jeffrey M. Voit, Richard A. Sankaran, Vijay G. |
author_sort | Shen, Yong |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8530301 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-85303012021-10-22 Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing Shen, Yong Li, Rick Teichert, Kristian Montbleau, Kara E. Verboon, Jeffrey M. Voit, Richard A. Sankaran, Vijay G. PLoS Genet Research Article 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. Public Library of Science 2021-10-11 /pmc/articles/PMC8530301/ /pubmed/34634037 http://dx.doi.org/10.1371/journal.pgen.1009835 Text en © 2021 Shen et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Shen, Yong Li, Rick Teichert, Kristian Montbleau, Kara E. Verboon, Jeffrey M. Voit, Richard A. Sankaran, Vijay G. Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing |
title | Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing |
title_full | Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing |
title_fullStr | Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing |
title_full_unstemmed | Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing |
title_short | Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing |
title_sort | pathogenic bcl11a variants provide insights into the mechanisms of human fetal hemoglobin silencing |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530301/ https://www.ncbi.nlm.nih.gov/pubmed/34634037 http://dx.doi.org/10.1371/journal.pgen.1009835 |
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