Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis

被引:65
作者
McDermott, David H. [1 ]
De Ravin, Suk See [2 ]
Jun, Hyun Sik [3 ]
Liu, Qian [1 ]
Priel, Debra A. Long [4 ]
Noel, Pierre [5 ]
Takemoto, Clifford M. [6 ]
Ojode, Teresa [1 ]
Paul, Scott M. [7 ]
Dunsmore, Kimberly P. [8 ]
Hilligoss, Dianne [2 ]
Marquesen, Martha [2 ]
Ulrick, Jean [2 ]
Kuhns, Douglas B. [4 ]
Chou, Janice Y. [3 ]
Malech, Harry L. [2 ]
Murphy, Philip M. [1 ]
机构
[1] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA
[2] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA
[3] NICHHD, Sect Cellular Differentiat, NIH, Bethesda, MD 20892 USA
[4] NCI, Clin Serv Program, SAIC Frederick Inc, Frederick, MD 21701 USA
[5] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA
[6] Johns Hopkins Univ, Sch Med, Div Pediat Hematol, Baltimore, MD USA
[7] NIH, Dept Phys Med & Rehabil, Ctr Clin, Bethesda, MD 20892 USA
[8] Univ Virginia, Hlth Sci Ctr, Div Hematol Oncol, Dept Pediat, Charlottesville, VA USA
基金
美国国家卫生研究院;
关键词
CHRONIC GRANULOMATOUS-DISEASE; G-CSF; BONE-MARROW; MUTATIONS; PROTEIN; GENE; MOBILIZATION; CELLS; ELA2; ELASTASE;
D O I
10.1182/blood-2010-01-265942
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Mutations in more than 15 genes are now known to cause severe congenital neutropenia (SCN); however, the pathologic mechanisms of most genetic defects are not fully defined. Deficiency of G6PC3, a glucose-6-phosphatase, causes a rare multisystem syndrome with SCN first described in 2009. We identified a family with 2 children with homozygous G6PC3 G260R mutations, a loss of enzymatic function, and typical syndrome features with the exception that their bone marrow biopsy pathology revealed abundant neutrophils consistent with myelokathexis. This pathologic finding is a hallmark of another type of SCN, WHIM syndrome, which is caused by gain-of-function mutations in CXCR4, a chemokine receptor and known neutrophil bone marrow retention factor. We found markedly increased CXCR4 expression on neutrophils from both our G6PC3-deficient patients and G6pc3(-/-) mice. In both patients, granulocyte colony-stimulating factor treatment normalized CXCR4 expression and neutrophil counts. In G6pc3(-/-) mice, the specific CXCR4 antagonist AMD3100 rapidly reversed neutropenia. Thus, myelokathexis associated with abnormally high neutrophil CXCR4 expression may contribute to neutropenia in G6PC3 deficiency and responds well to granulocyte colony-stimulating factor. (Blood.2010;116(15):2793-2802)
引用
收藏
页码:2793 / 2802
页数:10
相关论文
共 36 条
[1]   Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia [J].
Ancliff, Phil J. ;
Blundell, Michael P. ;
Cory, Giles O. ;
Calle, Yolanda ;
Worth, Austen ;
Kempski, Helena ;
Burns, Siobhan ;
Jones, Gareth E. ;
Sinclair, Jo ;
Kinnon, Christine ;
Hann, Ian M. ;
Gale, Rosemary E. ;
Linch, David C. ;
Thrasher, Adrian J. .
BLOOD, 2006, 108 (07) :2182-2189
[2]   A novel G6PC3 homozygous 1-bp deletion as a cause of severe congenital neutropenia [J].
Arostegui, Juan I. ;
Sanchez de Toledo, Jose ;
Pascal, Mariona ;
Garcia, Carlos ;
Yaguee, Jordi ;
Diaz de Heredia, Cristina .
BLOOD, 2009, 114 (08) :1718-1719
[3]   Evaluation of role of G-CSF in the production, survival, and release of neutrophils from bone marrow into circulation [J].
Basu, S ;
Hodgson, G ;
Katz, M ;
Dunn, AR .
BLOOD, 2002, 100 (03) :854-861
[4]   Severe congenital neutropenia: new genes explain an old disease [J].
Bohn, Georg ;
Welte, Karl ;
Klein, Christoph .
CURRENT OPINION IN RHEUMATOLOGY, 2007, 19 (06) :644-650
[5]   A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14 [J].
Bohn, Georg ;
Allroth, Anna ;
Brandes, Gudrun ;
Thiel, Jens ;
Glocker, Erik ;
Schaffer, Alejandro A. ;
Rathinam, Chozhavendan ;
Taub, Nicole ;
Teis, David ;
Zeidler, Cornelia ;
Dewey, Ricardo A. ;
Geffers, Robert ;
Buer, Jan ;
Huber, Lukas A. ;
Welte, Karl ;
Grimbacher, Bodo ;
Klein, Christoph .
NATURE MEDICINE, 2007, 13 (01) :38-45
[6]   A Syndrome with Congenital Neutropenia and Mutations in G6PC3 [J].
Boztug, Kaan ;
Appaswamy, Giridharan ;
Ashikov, Angel ;
Schaffer, Alejandro A. ;
Salzer, Ulrich ;
Diestelhorst, Jana ;
Germeshausen, Manuela ;
Brandes, Gudrun ;
Lee-Gossler, Jacqueline ;
Noyan, Fatih ;
Gatzke, Anna-Katherina ;
Minkov, Milen ;
Greil, Johann ;
Kratz, Christian ;
Petropoulou, Theoni ;
Pellier, Isabelle ;
Bellanne-Chantelot, Christine ;
Rezaei, Nima ;
Moenkemoeller, Kirsten ;
Irani-Hakimeh, Noha ;
Bakker, Hans ;
Gerardy-Schahn, Rita ;
Zeidler, Cornelia ;
Grimbacher, Bodo ;
Welte, Karl ;
Klein, Christoph .
NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (01) :32-43
[7]   Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase-β [J].
Cheung, Yuk Yin ;
Kim, So Youn ;
Yiu, Wai Han ;
Pan, Chi-Jiunn ;
Jun, Hyun-Sik ;
Ruef, Robert A. ;
Lee, Eric J. ;
Westphal, Heiner ;
Mansfield, Brian C. ;
Chou, Janice Y. .
JOURNAL OF CLINICAL INVESTIGATION, 2007, 117 (03) :784-793
[8]   FOCUS ON RESEARCH The Many Causes of Severe Congenital Neutropenia [J].
Dale, David C. ;
Link, Daniel C. .
NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (01) :3-5
[9]   Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia [J].
Dale, DC ;
Person, RE ;
Bolyard, AA ;
Aprikyan, AG ;
Bos, C ;
Bonilla, MA ;
Boxer, LA ;
Kannourakis, G ;
Zeidler, C ;
Welte, K ;
Benson, KF ;
Horwitz, M .
BLOOD, 2000, 96 (07) :2317-2322
[10]   Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia [J].
Devriendt, K ;
Kim, AS ;
Mathijs, G ;
Frints, SGM ;
Schwartz, M ;
Van den Oord, JJ ;
Verhoef, GEG ;
Boogaerts, MA ;
Fryns, JP ;
You, DQ ;
Rosen, MK ;
Vandenberghe, P .
NATURE GENETICS, 2001, 27 (03) :313-317