Plo et al. have identified the first inherited condition that boosts the number of neutrophils (page 1701).

The patient with the condition was an 18-year-old man suffering from systemic inflammation that triggered fever, rapid heartbeat, difficulty breathing, and other symptoms. Tests revealed that his blood teemed with neutrophils—around three times the normal number. Eleven other members of the patient's family also harbored an excess of circulating neutrophils (neutrophilia) but apparently suffered no ill effects from the copious cells. Why only one family member became ill is unclear.

The overabundance of neutrophils pointed to faulty signaling by granulocyte colony stimulating factor (G-CSF), which spurs neutrophil precursors to differentiate and divide. Although G-CSF levels weren't elevated, all 12 family members carried a mutation in the gene encoding the G-CSF receptor (G-CSF-R) that produced a single amino acid swap. To confirm that the mutation in G-CSF-R leads to excess neutrophils, Plo et al. engineered mouse bone marrow cells to produce the mutant G-CSF-R and transferred them into irradiated mice. Indeed, the animals developed neutrophilia.

The researchers found that the mutant receptors remain stuck together as dimers, rendering them permanently switched on. As a result, neutrophil precursors continually receive orders to proliferate and differentiate. ML