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Blood, 15 July 2006, Vol. 108, No. 2, pp. 493-500. Prepublished online as a Blood First Edition Paper on March 21, 2006; DOI 10.1182/blood-2005-11-4689. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 2005-11-4689v1 108/2/493    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Köllner, I. Articles by Beger, C. Search for Related Content PubMed PubMed Citation Articles by Köllner, I. Articles by Beger, C. Related Collections Hematopoiesis and Stem Cells Phagocytes Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response Inga Köllner, Beate Sodeik, Sabine Schreek, Holger Heyn, Nils von Neuhoff, Manuela Germeshausen, Cornelia Zeidler, Martin Krüger, Brigitte Schlegelberger, Karl Welte, and Carmela Beger From the Institute of Cell and Molecular Pathology, the Institute of Virology, the Department of Pediatric Hematology and Oncology, and the Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Severe congenital neutropenia (SCN) and cyclic neutropenia (CyN) are sporadic or inherited hematologic disorders of myelopoiesis. Heterozygous mutations in the gene encoding neutrophil elastase (ELA2) have been reported in both diseases. We used an inducible system to express a panel of ELA2 mutations and found for almost all mutants disruption of intracellular neutrophil elastase (HNE) protein processing at different levels. This disruption resulted in cytoplasmic accumulation of a nonfunctional protein, thereby preventing its physiologic transport to azurophil granules. Furthermore, the secretory capacity of the mutant proteins was greatly diminished, indicating alteration of the regulated and the constitutive pathways. Through analysis of primary granulocytes from SCN patients carrying ELA2 mutations, we found an identical pattern of intracellular accumulation of mutant HNE protein in the cytoplasm. Moreover, cells expressing mutant HNE protein exhibited a significant increase in apoptosis associated with up-regulation of the master ER chaperone BiP, indicating that disturbance of intracellular trafficking results in activation of the mammalian unfolded protein response. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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] D. S. Grenda, M. Murakami, J. Ghatak, J. Xia, L. A. Boxer, D. Dale, M. C. Dinauer, and D. C. Link Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis Blood, December 15, 2007; 110(13): 4179 - 4187. [Abstract] [Full Text] [PDF] D. A. Moulding, M. P. Blundell, D. G. Spiller, M. R.H. White, G. O. Cory, Y. Calle, H. Kempski, J. Sinclair, P. J. Ancliff, C. Kinnon, et al. Unregulated actin polymerization by WASp causes defects of mitosis and cytokinesis in X-linked neutropenia J. Exp. Med., September 3, 2007; 204(9): 2213 - 2224. [Abstract] [Full Text] [PDF] M. Donini, S. Fontana, G. Savoldi, W. Vermi, L. Tassone, F. Gentili, E. Zenaro, D. Ferrari, L. D. Notarangelo, F. Porta, et al. G-CSF treatment of severe congenital neutropenia reverses neutropenia but does not correct the underlying functional deficiency of the neutrophil in defending against microorganisms Blood, June 1, 2007; 109(11): 4716 - 4723. [Abstract] [Full Text] [PDF] M. S. Horwitz, Z. Duan, B. Korkmaz, H.-H. Lee, M. E. Mealiffe, and S. J. Salipante Neutrophil elastase in cyclic and severe congenital neutropenia Blood, March 1, 2007; 109(5): 1817 - 1824. [Abstract] [Full Text] [PDF] G. C. Bagby and G. Meyers Bone Marrow Failure as a Risk Factor for Clonal Evolution: Prospects for Leukemia Prevention Hematology, January 1, 2007; 2007(1): 40 - 46. [Abstract] [Full Text] [PDF]

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