title: Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.
abstract: 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.
authors.affiliation: Division of Oncology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Grenda
authors.forename: Mark
authors.initials: M
authors.lastname: Murakami
authors.forename: Jhuma
authors.initials: J
authors.lastname: Ghatak
authors.forename: Jun
authors.initials: J
authors.lastname: Xia
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Boxer
authors.forename: David
authors.initials: D
authors.lastname: Dale
authors.forename: Mary C
authors.initials: MC
authors.lastname: Dinauer
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
mesh_terms: D017209:Apoptosis; D000091342:Endoplasmic Reticulum Chaperone BiP; D042381:Granulocyte Precursor Cells / Q000166:cytology*; D006801:Humans; D019272:Leukocyte Elastase / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D038042:Myelopoiesis; D009503:Neutropenia / Q000151:congenital / Q000201:enzymology* / Q000235:genetics*; D011489:Protein Denaturation; D017510:Protein Folding
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D019272:Leukocyte Elastase