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Blood, 1 March 2007, Vol. 109, No. 5, pp. 1817-1824.
Prepublished online as a Blood First Edition Paper on October 19, 2006November 14, 2006; DOI 10.1182/blood-2006-08-019166.
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Submitted August 17, 2006
Accepted October 15, 2006
Neutrophil elastase in cyclic and severe congenital neutropenia
Marshall S. Horwitz*, Zhijun Duan, Brice Korkmaz, Hu-Hui Lee, Matthew E. Mealiffe, and Stephen J. Salipante
Division of Medical Genetics, Dept of Medicine, University of Washington School of Medicine, Seattle, WA
* Corresponding author; email: horwitz{at}u.washington.edu.
Mutations in ELA2, encoding the neutrophil granule protease, neutrophil elastase (NE), are the major cause of the two 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), and 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 three 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.
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