Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. 
Mutations of the ELA2 gene encoding neutrophil elastase (NE) are responsible for 
most cases of SCN and cyclic neutropenia (CN), a related but milder disorder of 
granulopoiesis. However, the mechanisms by which these mutations disrupt 
granulopoiesis are unclear. We hypothesize that the ELA2 mutations result in the 
production of misfolded NE protein, activation of the unfolded protein response 
(UPR), and ultimately apoptosis of granulocytic precursors. Expression of mutant 
NE but not wild-type NE strongly induced BiP/GRP78 mRNA expression and XBP1 mRNA 
splicing, 2 classic markers of the UPR. The magnitude of UPR activation by a 
specific ELA2 mutation correlated with its associated clinical phenotype. 
Consistent with the UPR model, expression of mutant NE in primary human 
granulocytic precursors increased expression of CHOP (DDITS) and induced 
apoptosis in a protease-independent fashion. Most strikingly, UPR activation and 
decreased NE protein expression were detected in primary granulocytic precursors 
from SCN patients. Collectively, these data provide strong support for a UPR 
model of SCN disease pathogenesis and place SCN in a growing list of human 
diseases caused by misfolded proteins.