Functional interaction between mutations in the granulocyte colony-stimulating factor receptor in severe congenital neutropenia

SummaryMost severe congenital neutropenia (SCN) cases possess constitutive neutrophil elastase mutations; a smaller cohort has acquired mutations truncating the granulocyte colony‐stimulating factor receptor (G‐CSF‐R). We have described a case with constitutive extracellular G‐CSF‐R mutation hyporesponsive to ligand. Here we report two independent acquired G‐CSF‐R truncation mutations and a novel constitutive neutrophil elastase mutation in this patient. Co‐expression of a truncated receptor chain restored STAT5 signalling responses of the extracellular G‐CSF‐R mutant, while constitutively‐active STAT5 enhanced its proliferative capacity. These data add to our knowledge of SCN and further highlight the importance of STAT5 in mediating proliferative responses to G‐CSF.