Severe congenital neutropenia and the unfolded protein response

Severe congenital neutropenia is an inborn disorder of granulopoiesis. Mutations of ELA2, encoding neutrophil elastase, are present in approximately 50% of cases of severe congenital neutropenia and nearly all cases of cyclic neutropenia, a related disorder of granulopoiesis. Herein, we review recent studies of the molecular pathogenesis of severe congenital neutropenia, with an emphasis on those cases associated with mutations of ELA2.

Genetic evidence suggests that ELA2 mutations act in a dominant, cell-intrinsic fashion to disrupt granulopoiesis. A unifying model that accounts for the different clinical phenotypes (severe congenital neutropenia versus cyclic neutropenia) and the diversity of ELA2 mutations (over 50 have been identified), however, is lacking. Recent studies suggest that mutations of ELA2 may cause disease through induction of the unfolded protein response. In this model, the ELA2 mutations result in the production of misfolded neutrophil elastase protein, activation of the unfolded protein response, and ultimately apoptosis of granulocytic precursors. The propensity of individual neutrophil elastase mutants to misfold may determine the magnitude of unfolded protein response-induced apoptosis and ultimately the clinical phenotype.

Recent studies provide support for a unfolded protein response model of disease pathogenesis in cases of severe congenital neutropenia associated with ELA2 mutations and place severe congenital neutropenia in a growing list of human disease caused by misfolded proteins.