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Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing.


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.

SUBMITTER: Shen Y 

PROVIDER: S-EPMC8530301 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing.

Shen Yong Y   Li Rick R   Teichert Kristian K   Montbleau Kara E KE   Verboon Jeffrey M JM   Voit Richard A RA   Sankaran Vijay G VG  

PLoS genetics 20211011 10


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 dele  ...[more]

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