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...

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Autores principales:	Yong Shen, Rick Li, Kristian Teichert, Kara E Montbleau, Jeffrey M Verboon, Richard A Voit, Vijay G Sankaran
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/16c4ace60f69490ea3d73aa1074950f0
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spelling	oai:doaj.org-article:16c4ace60f69490ea3d73aa1074950f02021-12-02T20:03:32ZPathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing.1553-73901553-740410.1371/journal.pgen.1009835https://doaj.org/article/16c4ace60f69490ea3d73aa1074950f02021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009835https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Increased 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.Yong ShenRick LiKristian TeichertKara E MontbleauJeffrey M VerboonRichard A VoitVijay G SankaranPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 10, p e1009835 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Yong Shen Rick Li Kristian Teichert Kara E Montbleau Jeffrey M Verboon Richard A Voit Vijay G Sankaran Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing.
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	article
author	Yong Shen Rick Li Kristian Teichert Kara E Montbleau Jeffrey M Verboon Richard A Voit Vijay G Sankaran
author_facet	Yong Shen Rick Li Kristian Teichert Kara E Montbleau Jeffrey M Verboon Richard A Voit Vijay G Sankaran
author_sort	Yong Shen
title	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_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_sort	pathogenic bcl11a variants provide insights into the mechanisms of human fetal hemoglobin silencing.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/16c4ace60f69490ea3d73aa1074950f0
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Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing.

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