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A novel mutation in the juxtamembrane intracellular sequence of the granulocyte colony-stimulating factor (G-CSF) receptor gene in a patient with severe congenital neutropenia augments G-CSF proliferation activity but not through the MAP kinase cascade

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Overview

authors

  • Yokoyama, T.
  • Okamura, S.
  • Asano, Y.
  • Kamezaki, K.
  • Numata, A.
  • Kakumitsu, H.
  • Shide, K.
  • Nakashima, H.
  • Kanaji, Taisuke
  • Sekine, Y.
  • Mizuno, Y.
  • Okamura, J.
  • Matsuda, T.
  • Harada, M.
  • Niho, Y.
  • Shimoda, K.

publication date

  • 2005

journal

  • International Journal of Hematology  Journal

abstract

  • We analyzed the structure of the granulocyte colony-stimulating factor (G-CSF) receptor gene in a 6-year-old female patient with severe congenital neutropenia (SCN) who experienced severe recurrent infections since 1 month of age. There is no family history of any similar disease. When the patient was 4 months old, she began receiving treatment with recombinant human G-CSF that resulted in a small increase in the neutrophil count sufficient for the prevention and treatment of bacterial infection. An analysis of complementary DNA for the patient's G-CSF receptor revealed a 3-base pair deletion in the juxtamembrane intracellular sequence. This deletion at the beginning of exon 16 was thought to be caused by alternative splicing; analysis of the DNA revealed a G-to-A point mutation of the final nucleotide of intron 15. To evaluate the functional activity of the G-CSF receptor with this 3-base pair deletion of the juxtamembrane region, we transfected this G-CSF receptor mutant into an interleukin 3-dependent cell line, BAF/3. BAF/3 cells expressing the mutant G-CSF receptor showed augmented proliferation activity in response to G-CSF compared with cells having the wild-type G-CSF receptor. Although the proliferation signal of G-CSF in normal hematopoiesis is transduced through the activation of MAP kinases, this G-CSF receptor mutant showed decreased activation of ERKI/2 in response to G-CSF compared with the wild type, but the transduced sig-nal for Stat3 activation by G-CSF was of the same magnitude as that of the wild-type G-CSF receptor. This result means that the augmented proliferation activity in response to G-CSF that we observed in cells having the G-CSF receptor gene with the 3-base pair deletion is transduced through an intracellular signaling pathway other than MAP kinase. Because SCN patients with a mutation in the G-CSF receptor frequently develop leukemia, this 3-base pair deletion in the juxtamembrane sequence of the G-CSF receptor gene in this patient may be one step in the course of leukemic transformation.

subject areas

  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Child
  • DNA
  • Female
  • Frameshift Mutation
  • History, Ancient
  • Humans
  • Leukemia
  • MAP Kinase Signaling System
  • Neutropenia
  • Receptors, Granulocyte Colony-Stimulating Factor
  • Signal Transduction
  • Syndrome
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Research

keywords

  • G-CSF receptor
  • MAP kinase
  • congenital neutropenia
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Identity

International Standard Serial Number (ISSN)

  • 0925-5710

Digital Object Identifier (DOI)

  • 10.1532/ijh97.05010

PubMed ID

  • 16229088
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Additional Document Info

start page

  • 28

end page

  • 34

volume

  • 82

issue

  • 1

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