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 ß-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 ß-thalassemia.

Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation.

Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and ß-thalassemia1. BCL11A represses the genes encoding HbF and regulates human hemoglobin switching through variation in its expression during development2-7. However, the mechanisms underlying the developmental expression of BCL11A remain mysterious. Here we show that BCL11A is regulated at the level of messenger RNA (mRNA) translation during human hematopoietic development. Despite decreased BCL11A protein synthesis earlier in development, BCL11A mRNA continues to be associated with ribosomes. Through unbiased genomic and proteomic analyses, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a pattern reciprocal to that of BCL11A, directly interacts with ribosomes and BCL11A mRNA. Furthermore, we show that BCL11A mRNA translation is suppressed by LIN28B through direct interactions, independently of its role in regulating let-7 microRNAs, and that BCL11A is the major target of LIN28B-mediated HbF induction. Our results reveal a previously unappreciated mechanism underlying human hemoglobin switching that illuminates new therapeutic opportunities.

Health literacy, health-related quality of life, and atrial fbrillation.

Atrial fbrillation (AF) is a chronic heart rhythm disorder associated with significant adverse outcomes. Health-related quality of life (HRQoL) is an established metric of health status in individuals with AF, and health literacy is highly relevant to how individuals experience HRQoL. We conducted a pilot investigation to examine the association of health literacy and health related quality of life (HRQoL) in a limited-sized cohort of individuals with AF, all of whom had AF and were ≥60 years old. We used the Short-Test of Functional Health Literacy in Adults to categorize participants by health literacy status. We used the SF-36 to examine HRQoL in eight subscales and two composite scores, and related health literacy to HRQoL. In our cohort of 40 participants with AF (45% female, age 77.9 ± 8.0 years), 62.5% had inadequate health literacy. However, we did not identify a significant association between health literacy and HRQoL. We expect our limited-sized sample is a chief limitation for why we did not see an association between health literacy and HRQoL in this convenience cohort. Further studies examining health literacy and its impact on patient-centered outcomes in AF are essential.