Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient
Lilian Varricchio,
Antanas Planutis,
Deepa Manwani,
Julie Jaffray,
W. Beau Mitchell,
Anna Rita Migliaccio,
James J. Bieker
Affiliations
Lilian Varricchio
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Antanas Planutis
Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA;
Deepa Manwani
Division of Hematology/Oncology, The Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
Julie Jaffray
Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
W. Beau Mitchell
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Anna Rita Migliaccio
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Dipartimento di Scienze Biomediche e NeuroMotorie, Alma Mater Studiorum, Università di Bologna, Bologna, Italy
James J. Bieker
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA;;Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Congenital dyserythropoietic anemia type IV is caused by a heterozygous mutation, Glu325Lys (E325K), in the KLF1 transcription factor. Molecular characteristics of this disease have not been clarified, partly due to its rarity. We expanded erythroid cells from a patient’s peripheral blood and analyzed its global expression pattern. We find that a large number of erythroid pathways are disrupted, particularly those related to membrane transport, globin regulation, and iron utilization. The altered genetics lead to significant deficits in differentiation. Glu325 is within the KLF1 zinc finger domain at an amino acid critical for site specific DNA binding. The change to Lys is predicted to significantly alter the target site recognition sequence, both by subverting normal recognition and by enabling interaction with novel sites. Consistent with this, we find high level ectopic expression of genes not normally present in the red cell. These altered properties explain patients’ clinical and phenotypic features, and elucidate the dominant character of the mutation.
