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Blood, 1 October 2006, Vol. 108, No. 7, pp. 2182-2189. Prepublished online as a Blood First Edition Paper on June 27, 2006; DOI 10.1182/blood-2006-01-010249. This Article Full Text (PDF) Supplemental Methods and Videos All Versions of this Article: blood-2006-01-010249v1 108/7/2182    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 Ancliff, P. J Articles by Thrasher, A. J Search for Related Content PubMed PubMed Citation Articles by Ancliff, P. J Articles by Thrasher, A. J Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 10, 2006 Accepted April 10, 2006 Two novel activating mutations in the Wiskott-Aldrich Syndrome protein resulting in congenital neutropenia Phil J Ancliff*, Michael P Blundell, Giles O Cory, Yolanda Calle, Austen Worth, Helena Kempski, Siobhan Burns, Gareth E Jones, Jo Sinclair, Christine Kinnon, Ian M Hann, Rosemary E Gale, David C Linch, and Adrian J Thrasher Department of Haematology, Great Ormond Street Hospital, London, UK Molecular Immunology Unit, Institute of Child Health, University College London, UK Department of Biochemistry, School of Medical Sciences, University of Bristol, UK The Randall Centre for Molecular Mechanisms of Cell Function, King's College London, UK Molecular Haematology Unit, Institute of Child Health, University College London, UK The Randall Centre for Molecular Royal Free and University College Medical School * Corresponding author; email: anclip{at}gosh.nhs.uk. Severe congenital neutropenia (SCN) is characterized by neutropenia, recurrent bacterial infections and maturation arrest in the bone marrow. Although many cases have mutations in the ELA2 gene encoding neutrophil elastase, a significant proportion remain undefined at a molecular level. A mutation (L270P) in the gene encoding the Wiskott-Aldrich Syndrome protein (WASp) resulting in an X-linked SCN kindred has been reported. We therefore screened the WAS gene in 14 young SCN males with wild-type ELA2 and identified two with novel mutations, one who presented with myelodysplasia (I294T) and the other with classical SCN (S272P). Both patients had defects of immunological function including a generalized reduction of lymphoid and natural killer cell numbers, reduced lymphocyte proliferation and abrogated phagocyte activity. In vitro culture of bone marrow progenitors demonstrated a profound reduction in neutrophil production and increased levels of apoptosis, consistent with an intrinsic disturbance of normal myeloid differentiation as the cause of the neutropenia. Both mutations resulted in increased WASp activity and produced marked abnormalities of cytoskeletal structure and dynamics. Furthermore, these results also suggest a novel cause of myelodysplasia and suggest that male children with myelodysplasia and disturbance of immunological function should be screened for such mutations. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Park and D. Cox Cdc42 Regulates Fc{gamma} Receptor-mediated Phagocytosis through the Activation and Phosphorylation of Wiskott-Aldrich Syndrome Protein (WASP) and Neural-WASP Mol. Biol. Cell, November 1, 2009; 20(21): 4500 - 4508. [Abstract] [Full Text] [PDF] C. Klein Molecular basis of congenital neutropenia Haematologica, October 1, 2009; 94(10): 1333 - 1336. [Full Text] [PDF] K. Beel and P. Vandenberghe G-CSF receptor (CSF3R) mutations in X-linked neutropenia evolving to acute myeloid leukemia or myelodysplasia Haematologica, October 1, 2009; 94(10): 1449 - 1452. [Abstract] [Full Text] [PDF] M. P. Blundell, G. Bouma, J. Metelo, A. Worth, Y. Calle, L. A. Cowell, L. S. Westerberg, D. A. Moulding, S. Mirando, C. Kinnon, et al. Phosphorylation of WASp is a key regulator of activity and stability in vivo PNAS, September 15, 2009; 106(37): 15738 - 15743. [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] M. Bosticardo, F. Marangoni, A. Aiuti, A. Villa, and M. Grazia Roncarolo Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome Blood, June 18, 2009; 113(25): 6288 - 6295. [Abstract] [Full Text] [PDF] C. S. Velu, A. M. Baktula, and H. L. Grimes Gfi1 regulates miR-21 and miR-196b to control myelopoiesis Blood, May 7, 2009; 113(19): 4720 - 4728. [Abstract] [Full Text] [PDF] L. D. Notarangelo and R. Badolato Leukocyte trafficking in primary immunodeficiencies J. Leukoc. Biol., March 1, 2009; 85(3): 335 - 343. [Abstract] [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] D. E. Montoya-Durango, C. S. Velu, A. Kazanjian, M. E. B. Rojas, C. M. Jay, G. D. Longmore, and H. L. Grimes Ajuba Functions as a Histone Deacetylase-dependent Co-repressor for Autoregulation of the Growth Factor-independent-1 Transcription Factor J. Biol. Chem., November 14, 2008; 283(46): 32056 - 32065. [Abstract] [Full Text] [PDF] G P Spickett Immune deficiency disorders involving neutrophils J. Clin. Pathol., September 1, 2008; 61(9): 1001 - 1005. [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] 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. S. Horwitz, Z. Duan, B. Korkmaz, H.-H. Lee, M. E. Mealiffe, and S. J. 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