KLF1 (Krüppel-like factor 1) is an erythroid transcription factor involved in various stages of red blood cell formation. KLF1 plays key functions at the megakaryocyte-erythrocyte progenitor stage, where it is involved in the development of the erythrocyte lineage. It participates in the global expression of erythrocyte genes, playing a direct role in globin switching. KLF1 also participates in the final maturation of erythrocytes, controlling exit from the cell cycle and the enucleation process. KLF1 has a domain structure: N-terminal transactivation domain and C-terminal DNA-binding domain. Many variants (mutations) have been described in the KLF1 gene, which lead to the development of a whole spectrum of phenotypes: from clinically insignificant morphological changes, through mild changes, to severe pathological conditions. Two mutations are dominant. One occurs in mice and causes neonatal anemia with congenital spherocytosis (Nan), the other in humans and leads to congenital dyserythropoietic anemia type IV (CDA). KLF1 (Krüppel-like factor 1) jest erytroidalnym czynnikiem transkrypcyjnym zaangażowanym w różnorodne etapy tworzenia czerwonych krwinek.  KLF1 odgrywa kluczowe funkcje na etapie progenitora megakariocytów-erytrocytów, gdzie zaangażowany jest w rozwój linii erytrocytów. Uczestniczy podczas globalnej ekspresji genów erytrocytów odgrywając bezpośrednią rolę w przełączaniu globiny. KLF1 bierze też udział podczas końcowego dojrzewania erytrocytów kontrolując wyjście z cyklu komórkowego, jak też proces enukleacji. KLF1 ma on budowę domenową: N-końcowa transaktywacyjna oraz C-końcowa domena wiążąca DNA.  W genie KLF1 opisano wiele mutacji, które prowadzą do powstania całego spektrum fenotypów: od klinicznie nieistotnych zmian morfologicznych, przez łagodne zmiany, aż po ciężkie stany patologiczne. Dwie mutacje mają charakter dominującym. Jedna występuje u myszy i powoduje anemię noworodkową ze sferocytozą wrodzoną (Nan), druga u ludzi i prowadzi do wrodzonej anemii dyserytropoetycznej typu IV (CDA).

Erythroid Krüppel-like factor (KLF1), first discovered in 1992, is an erythroid-restricted transcription factor (TF) that is essential for terminal differentiation of erythroid progenitors. At face value, KLF1 is a rather inconspicuous member of the 26-strong SP/KLF TF family. However, 30 years of research have revealed that KLF1 is a jack of all trades in the molecular control of erythropoiesis. Initially described as a one-trick pony required for high-level transcription of the adult HBB gene, we now know that it orchestrates the entire erythroid differentiation program. It does so not only as an activator but also as a repressor. In addition, KLF1 was the first TF shown to be directly involved in enhancer/promoter loop formation. KLF1 variants underlie a wide range of erythroid phenotypes in the human population, varying from very mild conditions such as hereditary persistence of fetal hemoglobin and the In(Lu) blood type in the case of haploinsufficiency, to much more serious non-spherocytic hemolytic anemias in the case of compound heterozygosity, to dominant congenital dyserythropoietic anemia type IV invariably caused by a de novo variant in a highly conserved amino acid in the KLF1 DNA-binding domain. In this chapter, we present an overview of the past and present of KLF1 research and discuss the significance of human KLF1 variants.

Congenital dyserythropoietic anemia type IV (CDAIV) is a rare inherited hematological disorder, presenting with severe anemia due to altered erythropoiesis and hemolysis, with variable needs for recurrent transfusions. We present a case of a transfusion-dependent male newborn who presented at birth with severe hemolytic anemia, and required an intrauterine transfusion. Genetic testing rapidly identified a Kruppel-like factor 1 (KLF1) pathogenic variant (c.973G>A, p.E325K), known to be causative for CDAIV. This case highlights the advantages of next-generation sequencing testing for congenital hemolytic anemia: diagnostic speed, guidance on natural history, and optimized clinical management and anticipatory guidance for parents and clinicians. Additionally, we reviewed the literature for all CDAIV cases.