A Dominant Mutation in the Gene Encoding the Erythroid Transcription Factor KLF1 Causes a Congenital Dyserythropoietic Anemia

Abstract

The congenital dyserythropoietic anemias (CDAs) are inherited red blood cell disorders whose hallmarks are ineffective erythropoiesis, hemolysis, and morphological abnormalities of erythroblasts in bone marrow. We have identified a missense mutation in KLF1 of patients with a hitherto unclassified CDA. KLF1 is an erythroid transcription factor, and extensive studies in mouse models have shown that it plays a critical role in the expression of globin genes, but also in the expression of a wide spectrum of genes potentially essential for erythropoiesis. The unique features of this CDA confirm the key role of KLF1 during human erythroid differentiation. Furthermore, we show that the mutation has a dominant-negative effect on KLF1 transcriptional activity and unexpectedly abolishes the expression of the water channel AQP1 and the adhesion molecule CD44. Thus, the study of this disease-causing mutation in KLF1 provides further insights into the roles of this transcription factor during erythropoiesis in humans.

Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin

“…KLF1 mutations can lead to loss or gain-of-function, giving rise to distinct phenotypic states, including CDA IV, CNSHA, and mild anemia, and induce increases in HbF level. [12][13][14] In contrast, the patients in this study exhibited the thalassemia phenotypes and unusual changes associated with KLF1 loss-of-function mutations. For instance, the microcytic hypochromic anemia with poikiloblast and abnormal heterochromatin organization in erythroblasts are not observed in CDA IV.…”

“…CDA IV combines features of hemoglobinopathy, red blood cell (RBC) membrane defects, and hereditary persistence of fetal hemoglobin (HPFH), which are not seen in the other types of CDA. 11,12 However, various mutations in human KLF1 have been described that are associated with benign phenotypes. Compound heterozygotes for KLF1 mutations are associated with both benign and disease phenotypes.…”

Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice

“…16,17 Furthermore, Klf1 knockout embryos carrying a human b-globin locus transgene fail to activate the human b-globin gene, while the g-globin genes are fully expressed. 18,19 Mutations in human KLF1 are associated with a spectrum of phenotypes, such as the In(Lu) blood group, 20 zinc protoporphyria, 21 increased HbA2, 22 congenital dyserythropoietic anemia (CDA), 23 and hereditary persistence fetal hemoglobin (HPFH). 13 Analysis of the HPFH phenotype has led to the proposal that KLF1 has a dual role in g-globin suppression through its preferential activation of the b-globin gene and as a key activator of expression of the BCL11A repressor protein.…”

“…13 A dominant KLF1 missense mutation p.E325K also affects DNA binding and was reported to cause CDA. 23 The two CDA patients with the p.E325K mutation displayed HbF levels of 31.6% and 44%. Remarkably, embryonic z-and e-globin were also increased to very high levels.…”

“…Remarkably, embryonic z-and e-globin were also increased to very high levels. 23 The ethylnitrosurea-induced mouse mutant Nan (neonatal anemia) carries a missense mutation, p.E339D, in the homologous position of mouse KLF1. 39,40 This mutation causes a dominant hemolytic anemia, with markedly increased expression of embryonic globins in adult Nan animals.…”