PMID- 10449521
OWN - NLM
STAT- MEDLINE
DCOM- 19990910
LR  - 20190508
IS  - 0022-1007 (Print)
IS  - 0022-1007 (Linking)
VI  - 190
IP  - 4
DP  - 1999 Aug 16
TI  - 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.
PG  - 497-507
AB  - 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.
FAU - Ward, A C
AU  - Ward AC
AD  - Institute of Hematology, Erasmus University Rotterdam, 3000 DR Rotterdam, The
      Netherlands. ward@hema.fgg.eur.nl
FAU - van Aesch, Y M
AU  - van Aesch YM
FAU - Gits, J
AU  - Gits J
FAU - Schelen, A M
AU  - Schelen AM
FAU - de Koning, J P
AU  - de Koning JP
FAU - van Leeuwen, D
AU  - van Leeuwen D
FAU - Freedman, M H
AU  - Freedman MH
FAU - Touw, I P
AU  - Touw IP
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (Ligands)
RN  - 0 (Receptors, Granulocyte Colony-Stimulating Factor)
RN  - 143011-72-7 (Granulocyte Colony-Stimulating Factor)
SB  - IM
MH  - Bone Marrow Cells/metabolism
MH  - Cell Division
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Granulocyte Colony-Stimulating Factor/metabolism/*therapeutic use
MH  - Humans
MH  - Infant
MH  - Ligands
MH  - Models, Molecular
MH  - Neutropenia/*congenital/*drug therapy
MH  - *Point Mutation
MH  - Protein Binding
MH  - Receptors, Granulocyte Colony-Stimulating Factor/*genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Sequence Analysis, DNA
MH  - Signal Transduction
PMC - PMC2195597
EDAT- 1999/08/17 00:00
MHDA- 1999/08/17 00:01
CRDT- 1999/08/17 00:00
PHST- 1999/08/17 00:00 [pubmed]
PHST- 1999/08/17 00:01 [medline]
PHST- 1999/08/17 00:00 [entrez]
AID - 10.1084/jem.190.4.497 [doi]
PST - ppublish
SO  - J Exp Med. 1999 Aug 16;190(4):497-507. doi: 10.1084/jem.190.4.497.