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Mutations in linker-2 of KLF1 impair expression of membrane transporters and cytoskeletal proteins causing hemolysis

Author

Listed:
  • Stephen Huang

    (The University of Queensland
    The University of Queensland)

  • Casie Reed

    (Monash University)

  • Melissa Ilsley

    (The University of Queensland
    The University of Queensland)

  • Graham Magor

    (The University of Queensland
    Monash University)

  • Michael Tallack

    (The University of Queensland)

  • Michael Landsberg

    (The University of Queensland)

  • Helen Mitchell

    (Monash University)

  • Kevin Gillinder

    (The University of Queensland
    Monash University)

  • Andrew Perkins

    (The University of Queensland
    The University of Queensland
    Monash University
    The Alfred Hospital)

Abstract

The SP/KLF family of transcription factors harbour three C-terminal C2H2 zinc fingers interspersed by two linkers which confers DNA-binding to a 9-10 bp motif. Mutations in KLF1, the founding member of the family, are common. Missense mutations in linker two result in a mild phenotype. However, when co-inherited with loss-of-function mutations, they result in severe non-spherocytic hemolytic anemia. We generate a mouse model of this disease by crossing Klf1+/− mice with Klf1H350R/+ mice that harbour a missense mutation in linker-2. Klf1H350R/− mice exhibit severe hemolysis without thalassemia. RNA-seq demonstrate loss of expression of genes encoding transmembrane and cytoskeletal proteins, but not globins. ChIP-seq show no change in DNA-binding specificity, but a global reduction in affinity, which is confirmed using recombinant proteins and in vitro binding assays. This study provides new insights into how linker mutations in zinc finger transcription factors result in different phenotypes to those caused by loss-of-function mutations.

Suggested Citation

  • Stephen Huang & Casie Reed & Melissa Ilsley & Graham Magor & Michael Tallack & Michael Landsberg & Helen Mitchell & Kevin Gillinder & Andrew Perkins, 2024. "Mutations in linker-2 of KLF1 impair expression of membrane transporters and cytoskeletal proteins causing hemolysis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50579-4
    DOI: 10.1038/s41467-024-50579-4
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    1. Irène Aksoy & Vincent Giudice & Edwige Delahaye & Florence Wianny & Maxime Aubry & Magali Mure & Jiaxuan Chen & Ralf Jauch & Gireesh K. Bogu & Tobias Nolden & Heinz Himmelbauer & Michael Xavier Doss &, 2014. "Klf4 and Klf5 differentially inhibit mesoderm and endoderm differentiation in embryonic stem cells," Nature Communications, Nature, vol. 5(1), pages 1-15, September.
    2. Ermelinda Porpiglia & Daniel Hidalgo & Miroslav Koulnis & Abraham R Tzafriri & Merav Socolovsky, 2012. "Stat5 Signaling Specifies Basal versus Stress Erythropoietic Responses through Distinct Binary and Graded Dynamic Modalities," PLOS Biology, Public Library of Science, vol. 10(8), pages 1-19, August.
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