Figure 1
Figure 1. Biallelic CSF3R mutations detected in the CN patient leading to the absence of G-CSFR surface expression and G-CSF unresponsiveness. (A) Schematic representation of the wild-type G-CSFR and the mutant G-CSFR in the CN patient. The wild-type G-CSFR is composed of an extracellular part, a transmembrane region, and an intracellular domain. The extracellular part of the receptor includes an immunoglobulin (Ig)-like module, the cytokine receptor homology domain, and 3 fibronectin type III modules. Upon G-CSF binding to its receptor, a 2:2 tetrameric complex is formed. The intracellular domain is essential for the transduction of proliferation and differentiation signals. Both mutations identified in the CN patient alter the G-CSFR molecular composition either by creating a premature stop-codon or by shifting the codon frame and introducing spurious amino acids. (B) Absence of G-CSFR expression on the surface of the patient’s granulocytes and monocytes. The patient and healthy donor blood samples were stained with an allophycocyanin (APC)-conjugated anti-G-CSFR antibody, and surface G-CSFR expression on the patient’s granulocytes and monocytes was measured by flow cytometry. No surface expression of G-CSFR protein was detected. Cells from healthy donors were used as a positive control (ctrl). Representative histograms showing G-CSFR staining in the CN patient and healthy donor are depicted. (C) ANC and response to GM-CSF/G-CSF in the CN patient during the course of treatment. After 7 months of G-CSF administration, the patient still failed to produce neutrophils in an amount sufficient to protect against recurrent bacterial infection. After GM-CSF administration, the patient’s neutrophil count rose significantly to more than 1000 cells per microliter (range, 860-3744 cells per microliter), allowing the GM-CSF dose to be reduced to 3 µg/kg twice a week. After 6 months of successful treatment with GM-CSF, the patient was again prescribed G-CSF. Because G-CSF therapy produced no effect on neutrophil count, it was replaced with GM-CSF therapy (data not shown).

Biallelic CSF3R mutations detected in the CN patient leading to the absence of G-CSFR surface expression and G-CSF unresponsiveness. (A) Schematic representation of the wild-type G-CSFR and the mutant G-CSFR in the CN patient. The wild-type G-CSFR is composed of an extracellular part, a transmembrane region, and an intracellular domain. The extracellular part of the receptor includes an immunoglobulin (Ig)-like module, the cytokine receptor homology domain, and 3 fibronectin type III modules. Upon G-CSF binding to its receptor, a 2:2 tetrameric complex is formed. The intracellular domain is essential for the transduction of proliferation and differentiation signals. Both mutations identified in the CN patient alter the G-CSFR molecular composition either by creating a premature stop-codon or by shifting the codon frame and introducing spurious amino acids. (B) Absence of G-CSFR expression on the surface of the patient’s granulocytes and monocytes. The patient and healthy donor blood samples were stained with an allophycocyanin (APC)-conjugated anti-G-CSFR antibody, and surface G-CSFR expression on the patient’s granulocytes and monocytes was measured by flow cytometry. No surface expression of G-CSFR protein was detected. Cells from healthy donors were used as a positive control (ctrl). Representative histograms showing G-CSFR staining in the CN patient and healthy donor are depicted. (C) ANC and response to GM-CSF/G-CSF in the CN patient during the course of treatment. After 7 months of G-CSF administration, the patient still failed to produce neutrophils in an amount sufficient to protect against recurrent bacterial infection. After GM-CSF administration, the patient’s neutrophil count rose significantly to more than 1000 cells per microliter (range, 860-3744 cells per microliter), allowing the GM-CSF dose to be reduced to 3 µg/kg twice a week. After 6 months of successful treatment with GM-CSF, the patient was again prescribed G-CSF. Because G-CSF therapy produced no effect on neutrophil count, it was replaced with GM-CSF therapy (data not shown).

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