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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4179-4187. Prepublished online as a Blood First Edition Paper on August 30, 2007; DOI 10.1182/blood-2006-11-057299. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2006-11-057299v1 110/13/4179    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Grenda, D. S Articles by Link, D. C Search for Related Content PubMed PubMed Citation Articles by Grenda, D. S Articles by Link, D. C Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 9, 2006 Accepted August 23, 2007 Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis David S Grenda, Mark Murakami, Jhuma Ghatak, Jun Xia, Laurence A Boxer, David Dale, Mary C Dinauer, and Daniel C Link* Division of Oncology, Washington University School of Medicine, St. Louis, MO Div of Pediatric Hematology/Oncology, Dept of Pediatrics, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MI Department of Medicine, University of Washington, Seattle, WA Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indiana, IN * Corresponding author; email: dlink{at}im.wustl.edu. 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, two 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 disease caused by misfolded proteins. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Klein Molecular basis of congenital neutropenia Haematologica, October 1, 2009; 94(10): 1333 - 1336. [Full Text] [PDF] J. Skokowa, J. P. Fobiwe, L. Dan, B. K. Thakur, and K. Welte Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1 Blood, October 1, 2009; 114(14): 3044 - 3051. [Abstract] [Full Text] [PDF] S. J. Salipante, M. E. B. Rojas, B. Korkmaz, Z. Duan, J. Wechsler, K. F. Benson, R. E. Person, H. L. Grimes, and M. S. Horwitz Contributions to Neutropenia from PFAAP5 (N4BP2L2), a Novel Protein Mediating Transcriptional Repressor Cooperation between Gfi1 and Neutrophil Elastase Mol. Cell. Biol., August 15, 2009; 29(16): 4394 - 4405. [Abstract] [Full Text] [PDF] D. C. Dale and D. C. Link The Many Causes of Severe Congenital Neutropenia N. Engl. J. Med., January 1, 2009; 360(1): 3 - 5. [Full Text] [PDF] K. Boztug, G. Appaswamy, A. Ashikov, A. A. Schaffer, U. Salzer, J. Diestelhorst, M. Germeshausen, G. Brandes, J. Lee-Gossler, F. Noyan, et al. A Syndrome with Congenital Neutropenia and Mutations in G6PC3 N. Engl. J. Med., January 1, 2009; 360(1): 32 - 43. [Abstract] [Full Text] [PDF] N. Berliner Lessons from congenital neutropenia: 50 years of progress in understanding myelopoiesis Blood, June 15, 2008; 111(12): 5427 - 5432. [Abstract] [Full Text] [PDF] S. Y. Kim, H. S. Jun, P. A. Mead, B. C. Mansfield, and J. Y. Chou Neutrophil stress and apoptosis underlie myeloid dysfunction in glycogen storage disease type Ib Blood, June 15, 2008; 111(12): 5704 - 5711. [Abstract] [Full Text] [PDF]

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