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

Severe congenital neutropenia (SCN) is a heterogeneous condition characteri zed by a drastic reduction in circulating neutrophils and a maturation arre st of myeloid progenitor cells in the bone marrow. Usually this condition c an be successfully treated with granulocyte colony-stimulating factor (G-CS F). Here we describe the identification of a novel point mutation in the ex tracellular domain of the G-CSF receptor (G-CSF-R) in an SCN patient who fa iled 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 signa ling. This correlated with diminished activation of the receptor complex as determined by signal transducer and activator of transcription (STAT) acti vation, although activation of STAT5 was more affected than STAT3. Interest ingly, 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-recep tor complex formation with severe consequences for intracellular signal tra nsduction. Together these data add to our understanding of the mechanisms o f cytokine receptor signaling, emphasize the role of GCSFR-mutations in the etiology of SCN, and implicate such mutations in G-CSF hyporesponsiveness.