KLF1 – Congenital Dyserythropoietic Anemia Type IV

Kruppel-like factor 1 KLF1 is an erythroid-specific transcription factor essential for globin switching and red cell maturation. Monoallelic missense mutations in the second zinc finger domain, in particular c.973G>A (p.Glu325Lys), cause a distinct form of congenital dyserythropoietic anemia now defined as Congenital Dyserythropoietic Anemia Type IV (CDA IV).

Clinically, affected individuals present with severe hemolytic anemia often manifesting prenatally as hydrops fetalis (HP:0001789) and requiring intrauterine or chronic transfusions. Partial response to splenectomy, variable splenomegaly, elevated fetal hemoglobin, dyserythropoiesis on bone marrow exam, and occasional sex reversal have been reported, highlighting phenotypic heterogeneity (4 probands) (PMID:29300242; PMID:36798023; PMID:23522491; PMID:30876823).

Inheritance is autosomal dominant, with each proband harboring a de novo or sporadic heterozygous c.973G>A (p.Glu325Lys) mutation. No multi-generation segregation has been documented. Four unrelated cases define the core genetic evidence for CDA IV.

Functional analyses reveal that the E325K substitution perturbs DNA binding. In vitro binding assays show reduced affinity of mutant KLF1 for canonical CACCC motifs, particularly at the β-globin promoter, providing a molecular basis for impaired transactivation (PMID:21778342).

Patient-derived induced pluripotent stem cell (iPSC) models and ex vivo erythroid cultures demonstrate that KLF1-E325K causes G1 cell cycle arrest, dysregulation of cell cycle regulators (e.g., CDKN2A, CDKN2C), and altered expression of erythrocyte membrane and metabolic genes (e.g., EPB41, EPB42, GSR) consistent with dyserythropoiesis (PMID:30876823; PMID:30872368). ChIP-seq data further confirm neomorphic binding to noncanonical sites and ectopic transcription.

Together, genetic and experimental data support a dominant neomorphic mechanism by which KLF1-E325K disrupts erythroid transcriptional networks to cause CDA IV. Molecular diagnosis via next-generation sequencing enables rapid identification, informs prognosis, and guides transfusion and splenectomy decisions. KLF1 testing is recommended in unexplained neonatal hemolysis with dyserythropoiesis.

References

• Journal of pediatric hematology/oncology • 2018 • KLF1 E325K-associated Congenital Dyserythropoietic Anemia Type IV: Insights Into the Variable Clinical Severity. PMID:29300242
• Pediatric blood & cancer • 2023 • Congenital dyserythropoietic anemia type IV in the genetic era: A rare neonatal case report of rapid identification with a review of the literature. PMID:36798023
• Blood cells, molecules & diseases • 2013 • Erythroid transcription factor EKLF/KLF1 mutation causing congenital dyserythropoietic anemia type IV in a patient of Taiwanese origin: review of all reported cases and development of a clinical diagnostic paradigm. PMID:23522491
• Experimental hematology • 2019 • KLF1 mutation E325K induces cell cycle arrest in erythroid cells differentiated from congenital dyserythropoietic anemia patient-specific induced pluripotent stem cells. PMID:30876823
• Haematologica • 2019 • Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient. PMID:30872368
• Blood • 2011 • Mutations in the second zinc finger of human EKLF reduce promoter affinity but give rise to benign and disease phenotypes. PMID:21778342

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