title: 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 GCSF proliferation activity but not through the MAP kinase cascade.
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.
authors.affiliation: The First Department of Internal Medicine, Faculty of Medivine, Kyushu University, Fukuoka, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Seiichi
authors.initials: S
authors.lastname: Okamura
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Asano
authors.forename: Kenjirou
authors.initials: K
authors.lastname: Kamezaki
authors.forename: Akihiko
authors.initials: A
authors.lastname: Numata
authors.forename: Haruko
authors.initials: H
authors.lastname: Kakumitsu
authors.forename: Koutarou
authors.initials: K
authors.lastname: Shide
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Kanaji
authors.initials: K
authors.lastname: Taisuke
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sekine
authors.forename: Yumi
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Jun
authors.initials: J
authors.lastname: Okamura
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
authors.forename: Mine
authors.initials: M
authors.lastname: Harada
authors.forename: Niho
authors.initials: N
authors.lastname: Yoshiyuki
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
mesh_terms: D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002648:Child; D004247:DNA / Q000032:analysis; D005260:Female; D016368:Frameshift Mutation; D049690:History, Ancient; D006801:Humans; D007938:Leukemia / Q000235:genetics; D020935:MAP Kinase Signaling System; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics*; D015398:Signal Transduction; D013577:Syndrome
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor; D004247:DNA