Acquired and inherited CSF3R mutations associated with SCN. (A) The extracellular portion of the wild-type G-CSF receptor contains conserved domains including immunoglobulin-like (IG), cytokine region of homology (CRH), and fibronectin type 3 (FNIII) domains. The WSXWS motif in the CRH domain acts as a molecular switch during receptor activation. Following ligand binding, 4 tyrosine (Y) residues in the cytoplasmic domain are rapidly phosphorylated, forming binding sites for intracellular signaling molecules. (B) Acquired gain-of-function mutations that truncate the cytoplasmic domain are common in patients with SCN and are associated with hyperproliferation and leukemic transformation. (C) Somatic or de novo heterozygous mutations affecting the extracellular domain act in a dominant negative fashion by inhibiting receptor trafficking to the cell surface and oligomerization in response to G-CSF. (D) Inherited, biallelic loss-of-function mutations cause a distinctive variant of SCN characterized by full myeloid maturation in the bone marrow and refractoriness to G-CSF therapy.