{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:28:28Z","timestamp":1790821708665,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1009835","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T00:00:00Z","timestamp":1634774400000}}],"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T00:00:00Z","timestamp":1633910400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100003194","name":"New York Stem Cell Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003194","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lodish Family","award":["gift to Boston Children's Hospital"],"award-info":[{"award-number":["gift to Boston Children's Hospital"]}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK103794"],"award-info":[{"award-number":["R01 DK103794"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL146500"],"award-info":[{"award-number":["R01 HL146500"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R56 DK125234"],"award-info":[{"award-number":["R56 DK125234"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and \u03b2-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\u2019s 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<jats:italic>in vivo<\/jats:italic>illuminates mechanisms by which BCL11A silences HbF and also suggests potential therapeutic avenues for HbF induction to treat sickle cell disease and \u03b2-thalassemia.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009835","type":"journal-article","created":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T20:56:09Z","timestamp":1633985769000},"page":"e1009835","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":25,"title":["Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing"],"prefix":"10.1371","volume":"17","author":[{"given":"Yong","family":"Shen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3098-0885","authenticated-orcid":true,"given":"Rick","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7610-0249","authenticated-orcid":true,"given":"Kristian","family":"Teichert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3650-9557","authenticated-orcid":true,"given":"Kara E.","family":"Montbleau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4454-6043","authenticated-orcid":true,"given":"Jeffrey 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