Investigation of the variable In(Lu) phenotype caused by <i>KLF1</i> variants

Fraser, Nicole S.; Knauth, Christine; Schoeman, Elizna M.; Moussa, Assia; Perkins, Andrew C.; Walsh, Tamara; Millard, Glenda; Dean, Melinda M.; Hyland, Catherine A.; Flower, Robert L.

doi:10.1111/trf.14926

Cited by 7 publications

(14 citation statements)

References 25 publications

(36 reference statements)

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“…In contrast, the compound heterozygous promoter variant (g.-148G>A*), Met39Leu* (115A>C*), Lys288Glu* (862A>G*), Trp318Cys* (954G>C*), Leu326Arg* (977T>G*), Phe348Leu (1042T>C), His353Tyr (1057C>T), all show low CD44. The 954G>C and 977T>G variants had lowered CD44 levels, which is in agreement with a previous study [29]. Similarly the 977T>G variant showed increased HbA2 but no elevated HbF [29].…”

Section: Discussionsupporting

confidence: 92%

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Novel variants in Krueppel Like Factor 1 that cause Persistence of Fetal Hemoglobin in In(Lu) individuals

Eernstman

Veldhuisen

Ligthart

et al. 2021

Preprint

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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. These KLF1 variants often lead to KLF1 haploinsufficiency. We screened a donor cohort of 55 Lutheran weak or negative donors for KLF1 variants. To discriminate between weak and negative Lutheran expression, a flow cytometry (FCM) assay was developed to detect Lu polymorphisms. The Lu(a-b-) (negative) donor group, showing a significant decreased CD44 (Indian blood group) expression, also showed increased HbF and HbA2 levels, with outliers expressing >5% HbF. KLF1 exons and promoter sequencing revealed variants in 80% of the Lutheran negative donors. Thirteen different variants plus one high frequency SNP (c.304T>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.

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Section: Discussionsupporting

confidence: 92%

“…The 954G>C and 977T>G variants had lowered CD44 levels, which is in agreement with a previous study [29]. Similarly the 977T>G variant showed increased HbA2 but no elevated HbF [29].…”

Section: Discussionsupporting

confidence: 92%

Novel variants in Krueppel Like Factor 1 that cause Persistence of Fetal Hemoglobin in In(Lu) individuals

Eernstman

Veldhuisen

Ligthart

et al. 2021

Preprint

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“…Interestingly, the search for possible mutations in an erythroid TF -that turned out to be KLF1- as a cause of the In(Lu) phenotype came from transcriptomic analyses showing that In(Lu) cells express reduced levels of many erythroid-specific genes associated with red cell maturation, including BCAM (encoding for the Lu antigen), ALAS2 , HBB , SLC4A1 , and CD44 (Singleton et al, 2008). More recently, extended serological and FACS analysis of In(Lu) samples also revealed a reduced expression of CD35 , ICAM4 , and CD147 (Fraser et al, 2018). Interestingly, in one single case the In(Lu) phenotype has been associated with a GATA1 mutation (X414R) (Singleton et al, 2013).…”

Section: Quantitative Mutations Of Klf1: Haploinsufficiency/hypomorphmentioning

confidence: 97%

The Pleiotropic Effects of GATA1 and KLF1 in Physiological Erythropoiesis and in Dyserythropoietic Disorders

2019

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In the last few years, the advent of new technological approaches has led to a better knowledge of the ontogeny of erythropoiesis during development and of the journey leading from hematopoietic stem cells (HSCs) to mature red blood cells (RBCs). Our view of a well-defined hierarchical model of hematopoiesis with a near-homogeneous HSC population residing at the apex has been progressively challenged in favor of a landscape where HSCs themselves are highly heterogeneous and lineages separate earlier than previously thought. The coordination of these events is orchestrated by transcription factors (TFs) that work in a combinatorial manner to activate and/or repress their target genes. The development of next generation sequencing (NGS) has facilitated the identification of pathological mutations involving TFs underlying hematological defects. The examples of GATA1 and KLF1 presented in this review suggest that in the next few years the number of TF mutations associated with dyserythropoietic disorders will further increase.

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“…variants [2,[26][27][28]. This insight has allowed for the use of anti-CD44 antibodies in mass-screening exercises to identify potential In(Lu) individuals [26,[29][30][31][32][33].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Genetic Variants Within the Erythroid Transcription Factor, KLF1, and Reduction of the Expression of Lutheran and Other Blood Group Antigens: Review of the In(Lu) Phenotype

Fraser

Knauth

Moussa

et al. 2019

Transfusion Medicine Reviews

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Erythroid-specific Krüppel-like factor 1, or KLF1, is an integral transcriptional activator for erythropoiesis. Genetic variants within KLF1 can result in a range of erythropoietic clinical phenotypes from benign to significant. The In(Lu) phenotype refers to changes in the quantitative expression of blood group associated red cell surface molecules due to KLF1 variants which are otherwise clinically benign.These clinically benign KLF1 variants are associated with a reduced expression of one or more red cell membrane proteins/carbohydrates that carry blood group antigens for the LU (Lutheran), IN (Indian), P1PK, LW (Landsteiner-Wiener), KN (Knops), OK, RAPH and I blood group systems. This is of significance during routine serologic blood typing when expression falls below the test sensitivity and therefore impacts on the ability to accurately detect the presence of affected blood group antigens. This is of clinical importance since the transfusion requirements for individuals with the

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Investigation of the variable In(Lu) phenotype caused by KLF1 variants

Cited by 7 publications

References 25 publications

Novel variants in Krueppel Like Factor 1 that cause Persistence of Fetal Hemoglobin in In(Lu) individuals

Novel variants in Krueppel Like Factor 1 that cause Persistence of Fetal Hemoglobin in In(Lu) individuals

The Pleiotropic Effects of GATA1 and KLF1 in Physiological Erythropoiesis and in Dyserythropoietic Disorders

Genetic Variants Within the Erythroid Transcription Factor, KLF1, and Reduction of the Expression of Lutheran and Other Blood Group Antigens: Review of the In(Lu) Phenotype

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