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

Abstract

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

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

“…CD44 (harboring the Indian blood group system) has been described as a KLF1 target gene 2 . In addition, variants in KLF1 have been shown to result in upregulation of fetal hemoglobin 9 , 23 and correlate with increased adult hemoglobin A2 24 . We further characterized the Lu weak/negative cohort (including individuals without KLF1 variants), by measuring CD44, (harboring the Diego blood group system) and), GPA (harboring MNS antigens) and band 3 expression levels by FCM (Fig.…”

“…These individuals should only receive Lu(a − b −). The mixed field nature of Lu agglutination reactions makes proper assessment of Lu weak and negative individuals difficult 9 . KLF1 also regulates specific beta-locus globin expression, either directly or through the actions of target genes encoding transcriptional regulators or chromatin remodelers like LRF and BCL11A 10 , 11 .…”

An insertion/deletion polymorphism in the KLF1 gene resulting in an In(Lu) phenotype

“…In(Lu) RBCs have been reported to lack CD38, 2, 3 as observed since the introduction of anti‐CD38 therapies 5 . This donor's fresh RBCs typed CD38+, suggesting there may be additional variability in In(Lu) phenotypes, 1 or the freezing and thawing of stored In(Lu) RBCs may cause loss of CD38 expression. Further investigation as to expression of CD38 on In(Lu) RBCs is warranted.…”

“…The KLF1 (Krüppel‐like factor 1) gene does not encode a blood group system but rather a transcription factor. Mutations in the gene are dominant and are associated with reduced expression of antigens in the Lutheran, Indian, P1PK, LW, KN, OK, RAPH, and I blood group systems, and the AnWj antigen 1 . KLF1 variants are most often revealed by the reduced, and often serologically undetectable, expression of Lutheran antigens and the phenotype is referred to as the dominant Lu(a–b–) phenotype: In(Lu).…”

Hyperhaemolysis in a pregnant woman with a homozygous β0‐thalassemia mutation and two genetic modifiers

“…The pathophysiology of hyperhaemolysis is unknown. Although the KLF1:c.519_525dup variant had been reported to cause an apparent dominantly inherited Lu(a‐b‐) phenotype and anti‐Lu a or anti‐Lu b could cause delayed haemolytic transfusion reactions (Fraser et al, 2019 ; Thornton & Grimsley, 2019 ), it was impossible that the hyperhaemolysis in the pregnant woman was due to transfusion of mismatched Lutheran‐typed red cells. Unlike the true Lu null phenotype, the Lu (a‐b‐) phenotype caused by KLF1 mutations is due to a great reduction, but not loss, in Lu antigens.…”