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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2372-2380
Number of pages9
JournalHaematologica
Volume104
Issue number12
DOIs
StatePublished - Dec 1 2019

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Congenital Dyserythropoietic Anemia
Erythroid Cells
Mutation
Globins
Zinc Fingers
Transcription Factors
Iron
Amino Acids
Membranes
DNA

ASJC Scopus subject areas

  • Hematology

Cite this

Varricchio, L., Planutis, A., Manwani, D., Jaffray, J., Mitchell, W. B., Migliaccio, A. R., & Bieker, J. J. (2019). Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient. Haematologica, 104(12), 2372-2380. https://doi.org/10.3324/haematol.2018.209858

Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient. / Varricchio, Lilian; Planutis, Antanas; Manwani, Deepa; Jaffray, Julie; Mitchell, W. Beau; Migliaccio, Anna Rita; Bieker, James J.

In: Haematologica, Vol. 104, No. 12, 01.12.2019, p. 2372-2380.

Research output: Contribution to journalArticle

Varricchio, L, Planutis, A, Manwani, D, Jaffray, J, Mitchell, WB, Migliaccio, AR & Bieker, JJ 2019, 'Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient', Haematologica, vol. 104, no. 12, pp. 2372-2380. https://doi.org/10.3324/haematol.2018.209858
Varricchio, Lilian ; Planutis, Antanas ; Manwani, Deepa ; Jaffray, Julie ; Mitchell, W. Beau ; Migliaccio, Anna Rita ; Bieker, James J. / Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient. In: Haematologica. 2019 ; Vol. 104, No. 12. pp. 2372-2380.
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