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.
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16 August 1999
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August 16 1999
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
Alister C. Ward,
Alister C. Ward
aFrom the Institute of Hematology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
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Yvette M. van Aesch,
Yvette M. van Aesch
aFrom the Institute of Hematology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
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Judith Gits,
Judith Gits
aFrom the Institute of Hematology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
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Anita M. Schelen,
Anita M. Schelen
bDepartment of Hematology, Dr. Daniel den Hoed Cancer Center, 3008 AE Rotterdam, The Netherlands
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John P. de Koning,
John P. de Koning
aFrom the Institute of Hematology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
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Daphne van Leeuwen,
Daphne van Leeuwen
bDepartment of Hematology, Dr. Daniel den Hoed Cancer Center, 3008 AE Rotterdam, The Netherlands
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Melvin H. Freedman,
Melvin H. Freedman
cDivision of Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
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Ivo P. Touw
Ivo P. Touw
aFrom the Institute of Hematology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
bDepartment of Hematology, Dr. Daniel den Hoed Cancer Center, 3008 AE Rotterdam, The Netherlands
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Alister C. Ward
aFrom the Institute of Hematology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
Yvette M. van Aesch
aFrom the Institute of Hematology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
Judith Gits
aFrom the Institute of Hematology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
Anita M. Schelen
bDepartment of Hematology, Dr. Daniel den Hoed Cancer Center, 3008 AE Rotterdam, The Netherlands
John P. de Koning
aFrom the Institute of Hematology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
Daphne van Leeuwen
bDepartment of Hematology, Dr. Daniel den Hoed Cancer Center, 3008 AE Rotterdam, The Netherlands
Melvin H. Freedman
cDivision of Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
Ivo P. Touw
aFrom the Institute of Hematology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
bDepartment of Hematology, Dr. Daniel den Hoed Cancer Center, 3008 AE Rotterdam, The Netherlands
1used in this paper: CRH, cytokine receptor homologous; RT, reverse transcription; SCN, severe congenital neutropenia; STAT, signal transducer and activator of transcription
Received:
February 01 1999
Revision Requested:
June 08 1999
Accepted:
June 15 1999
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 1999 The Rockefeller University Press
1999
The Rockefeller University Press
J Exp Med (1999) 190 (4): 497–508.
Article history
Received:
February 01 1999
Revision Requested:
June 08 1999
Accepted:
June 15 1999
Citation
Alister C. Ward, Yvette M. van Aesch, Judith Gits, Anita M. Schelen, John P. de Koning, Daphne van Leeuwen, Melvin H. Freedman, Ivo P. Touw; 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. J Exp Med 16 August 1999; 190 (4): 497–508. doi: https://doi.org/10.1084/jem.190.4.497
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