title: Novel point mutation in the extracellular domain of the granulocyte colony-stimulating factor (G-CSF) receptor in a case of severe congenital neutropenia hyporesponsive to G-CSF treatment.
abstract: Severe congenital neutropenia (SCN) is a heterogeneous condition characterized by a drastic reduction in circulating neutrophils and a maturation arrest of myeloid progenitor cells in the bone marrow. Usually this condition can be successfully treated with granulocyte colony-stimulating factor (G-CSF). Here we describe the identification of a novel point mutation in the extracellular domain of the G-CSF receptor (G-CSF-R) in an SCN patient who failed to respond to G-CSF treatment. When this mutant G-CSF-R was expressed in myeloid cells, it was defective in both proliferation and survival signaling. This correlated with diminished activation of the receptor complex as determined by signal transducer and activator of transcription (STAT) activation, although activation of STAT5 was more affected than STAT3. Interestingly, the mutant receptor showed normal affinity for ligand, but a reduced number of ligand binding sites compared with the wild-type receptor. This suggests that the mutation in the extracellular domain affects ligand-receptor complex formation with severe consequences for intracellular signal transduction. Together these data add to our understanding of the mechanisms of cytokine receptor signaling, emphasize the role of GCSFR mutations in the etiology of SCN, and implicate such mutations in G-CSF hyporesponsiveness.
authors.affiliation: Institute of Hematology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands. ward@hema.fgg.eur.nl
authors.forename: A C
authors.initials: AC
authors.lastname: Ward
authors.forename: Y M
authors.initials: YM
authors.lastname: van Aesch
authors.forename: J
authors.initials: J
authors.lastname: Gits
authors.forename: A M
authors.initials: AM
authors.lastname: Schelen
authors.forename: J P
authors.initials: JP
authors.lastname: de Koning
authors.forename: D
authors.initials: D
authors.lastname: van Leeuwen
authors.forename: M H
authors.initials: MH
authors.lastname: Freedman
authors.forename: I P
authors.initials: IP
authors.lastname: Touw
mesh_terms: D001854:Bone Marrow Cells / Q000378:metabolism; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D008024:Ligands; D008958:Models, Molecular; D009503:Neutropenia / Q000151:congenital* / Q000188:drug therapy*; D017354:Point Mutation; D011485:Protein Binding; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015398:Signal Transduction
chemical_list: D008024:Ligands; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor