Mutations in ELA2 encoding the neutrophil granule protease, neutrophil elastase 
(NE), are the major cause of the 2 main forms of hereditary neutropenia, cyclic 
neutropenia and severe congenital neutropenia (SCN). Genetic evaluation of other 
forms of neutropenia in humans and model organisms has helped to illuminate the 
role of NE. A canine form of cyclic neutropenia corresponds to human 
Hermansky-Pudlak syndrome type 2 (HPS2) and results from mutations in AP3B1 
encoding a subunit of a complex involved in the subcellular trafficking of 
vesicular cargo proteins (among which NE appears to be one). Rare cases of SCN 
are attributable to mutations in the transcriptional repressor Gfi1 (among whose 
regulatory targets also include ELA2). The ultimate biochemical consequences of 
the mutations are not yet known, however. Gene targeting of ELA2 has thus far 
failed to recapitulate neutropenia in mice. The cycling phenomenon and origins 
of leukemic transformation in SCN remain puzzling. Nevertheless, mutations in 
all 3 genes are capable of causing the mislocalization of NE and may also induce 
the unfolded protein response, suggesting that there might a convergent 
pathogenic mechanism focusing on NE.