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.

The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

“…Homozygous deletion of G-CSFR or G-CSF causes severe neutropenia in mice, 21,22 and heterozygous mutations of G-CSFR have been linked to sporadic cases of severe congenital neutropenia. 23 As both Gfi1 transcriptional regulation and G-CSF/ G-CSFR signaling are critical to neutrophil maturation, we have investigated whether their activities might be linked. We find that Gfi1 functions as a regulator of G-CSF/G-CSFR signaling in myeloid cells by promoting expression of RasGRP1 (Ras guanine nucleotide releasing protein 1), which is shown to be a critical modulator of G-CSF/G-CSFR-induced Ras activation.…”

Proteasomes Regulate the Duration of Erythropoietin Receptor Activation by Controlling Down-regulation of Cell Surface Receptors

“…Whether this mechanism could be responsible for increased responsiveness to growth factors observed in hematological disorders such as polycythemia vera remains to be determined. Interestingly, it has been recently shown that mutations in the G-CSF receptor that inhibit ligand-induced internalization and lead to extended receptor activation frequently occurred in acute myeloid leukemia (47,48),…”

Inherited biallelic CSF3R mutations in severe congenital neutropenia

“…15,16 Rarely, somatic or de novo heterozygous CSF3R mutations in the extracellular region of the G-CSFR have been described. [17][18][19][20] These mutants are characterized by hyporesponsiveness to rhG-CSF and act in a dominant-negative fashion by interfering with proper function of the wild-type (WT) G-CSFR. Additionally, a heterozygous germline CSF3R mutation has been associated with neutrophilia.…”