Novel variants in Krueppel like factor 1 that cause persistence of fetal hemoglobin in In(Lu) individuals

Abstract Beta-hemoglobinopathies become prominent after birth due to a switch from γ-globin to the mutated β-globin. Haploinsufficiency for the erythroid specific indispensable transcription factor Krueppel-like factor 1 (KLF1) is associated with high persistence of fetal hemoglobin (HPFH). The In(L...

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Autores principales:	Jesse Eernstman, Barbera Veldhuisen, Peter Ligthart, Marieke von Lindern, C. Ellen van der Schoot, Emile van den Akker
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9ee3cf0d7bf745ada041de96f847e1a5
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spelling	oai:doaj.org-article:9ee3cf0d7bf745ada041de96f847e1a52021-12-02T17:24:02ZNovel variants in Krueppel like factor 1 that cause persistence of fetal hemoglobin in In(Lu) individuals10.1038/s41598-021-97149-y2045-2322https://doaj.org/article/9ee3cf0d7bf745ada041de96f847e1a52021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97149-yhttps://doaj.org/toc/2045-2322Abstract Beta-hemoglobinopathies become prominent after birth due to a switch from γ-globin to the mutated β-globin. Haploinsufficiency for the erythroid specific indispensable transcription factor Krueppel-like factor 1 (KLF1) is associated with high persistence of fetal hemoglobin (HPFH). The In(Lu) phenotype, characterized by low to undetectable Lutheran blood group expression is caused by mutations within KLF1 gene. Here we screened a blood donor cohort of 55 Lutheran weak or negative donors for KLF1 variants and evaluated their effect on KLF1 target gene expression. To discriminate between weak and negative Lutheran expression, a flow cytometry (FCM) assay was developed to detect Lu antigen expression. The Lu(a−b−) (negative) donor group, showing a significant decreased CD44 (Indian blood group) expression, also showed increased HbF and HbA2 levels, with one individual expressing HbF as high as 5%. KLF1 exons and promoter sequencing revealed variants in 80% of the Lutheran negative donors. Thirteen different variants plus one high frequency SNP (c.304 T > C) were identified of which 6 were novel. In primary erythroblasts, knockdown of endogenous KLF1 resulted in decreased CD44, Lu and increased HbF expression, while KLF1 over-expressing cells were comparable to wild type (WT). In line with the pleiotropic effects of KLF1 during erythropoiesis, distinct KLF1 mutants expressed in erythroblasts display different abilities to rescue CD44 and Lu expression and/or to affect fetal (HbF) or adult (HbA) hemoglobin expression. With this study we identified novel KLF1 variants to be include into blood group typing analysis. In addition, we provide further insights into the regulation of genes by KLF1.Jesse EernstmanBarbera VeldhuisenPeter LigthartMarieke von LindernC. Ellen van der SchootEmile van den AkkerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jesse Eernstman Barbera Veldhuisen Peter Ligthart Marieke von Lindern C. Ellen van der Schoot Emile van den Akker Novel variants in Krueppel like factor 1 that cause persistence of fetal hemoglobin in In(Lu) individuals
description	Abstract Beta-hemoglobinopathies become prominent after birth due to a switch from γ-globin to the mutated β-globin. Haploinsufficiency for the erythroid specific indispensable transcription factor Krueppel-like factor 1 (KLF1) is associated with high persistence of fetal hemoglobin (HPFH). The In(Lu) phenotype, characterized by low to undetectable Lutheran blood group expression is caused by mutations within KLF1 gene. Here we screened a blood donor cohort of 55 Lutheran weak or negative donors for KLF1 variants and evaluated their effect on KLF1 target gene expression. To discriminate between weak and negative Lutheran expression, a flow cytometry (FCM) assay was developed to detect Lu antigen expression. The Lu(a−b−) (negative) donor group, showing a significant decreased CD44 (Indian blood group) expression, also showed increased HbF and HbA2 levels, with one individual expressing HbF as high as 5%. KLF1 exons and promoter sequencing revealed variants in 80% of the Lutheran negative donors. Thirteen different variants plus one high frequency SNP (c.304 T > C) were identified of which 6 were novel. In primary erythroblasts, knockdown of endogenous KLF1 resulted in decreased CD44, Lu and increased HbF expression, while KLF1 over-expressing cells were comparable to wild type (WT). In line with the pleiotropic effects of KLF1 during erythropoiesis, distinct KLF1 mutants expressed in erythroblasts display different abilities to rescue CD44 and Lu expression and/or to affect fetal (HbF) or adult (HbA) hemoglobin expression. With this study we identified novel KLF1 variants to be include into blood group typing analysis. In addition, we provide further insights into the regulation of genes by KLF1.
format	article
author	Jesse Eernstman Barbera Veldhuisen Peter Ligthart Marieke von Lindern C. Ellen van der Schoot Emile van den Akker
author_facet	Jesse Eernstman Barbera Veldhuisen Peter Ligthart Marieke von Lindern C. Ellen van der Schoot Emile van den Akker
author_sort	Jesse Eernstman
title	Novel variants in Krueppel like factor 1 that cause persistence of fetal hemoglobin in In(Lu) individuals
title_short	Novel variants in Krueppel like factor 1 that cause persistence of fetal hemoglobin in In(Lu) individuals
title_full	Novel variants in Krueppel like factor 1 that cause persistence of fetal hemoglobin in In(Lu) individuals
title_fullStr	Novel variants in Krueppel like factor 1 that cause persistence of fetal hemoglobin in In(Lu) individuals
title_full_unstemmed	Novel variants in Krueppel like factor 1 that cause persistence of fetal hemoglobin in In(Lu) individuals
title_sort	novel variants in krueppel like factor 1 that cause persistence of fetal hemoglobin in in(lu) individuals
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9ee3cf0d7bf745ada041de96f847e1a5
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Novel variants in Krueppel like factor 1 that cause persistence of fetal hemoglobin in In(Lu) individuals

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